Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof

ABSTRACT

Provided herein are compounds of the formulas (I) and (II): 
     
       
         
         
             
             
         
       
     
     as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.

FIELD OF THE INVENTION

The invention relates to Retinoic Acid Receptor-Related Orphan Receptor(ROR) regulated diseases and disorders. More particularly, the inventionrelates to ROR modulators; compositions comprising a therapeuticallyeffective amount of a ROR modulator; and methods for treating orpreventing ROR regulated diseases and disorders. All documents cited toor relied upon below are expressly incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

There are high unmet medical needs in the few established therapies forseveral autoimmune, inflammatory, metabolic and oncologic diseases.Despite the diverse clinical manifestations of these diseases, RetinoicAcid Receptor-Related Orphan Receptors (RORs) regulate and contribute tothe pathogenesis of these diseases through modulation of immuneresponses and lipid/glucose homeostasis. Only recently has the criticalregulatory role of RORs been well-characterized and target validated inseveral animal models of some of these diseases. RORs are transcriptionfactors which belong to the nuclear hormone receptor superfamily (Jetten(2009) Nucl. Recept. Signal., 7:e003; Jetten et al. (2013) FrontEndocrinol. (Lausanne), 4:1; Jetten & Joo (2006) Adv. Dev. Biol.,16:313-355). The ROR subfamily consists of three major isoforms: RORα(NR1F1), RORβ (NR1F2), and RORγ (NR1F3), encoded by the RORA, RORB andRORC genes, respectively. RORs are multidomain proteins that containfour principal domains typical of nuclear receptors: a highly variableN-terminal A/B domain, a highly conserved DNA-binding domain (DBD), aligand binding domain (LBD) that contains the ligand-dependentactivation function-2 (AF-2), and a hinge domain between the DBD andLBD. Each ROR gene through alternative splicing and promoter usagegenerates several ROR isoforms that differ only in their amino-terminus.In humans, there are four RORα isoforms (RORα1-4), one RORβ1 isoform,and two RORγ isoforms (RORγ1 and RORγ2 [RORγt]) that are expressed in ahighly tissue-specific manner. RORα and RORγ play an important role inthe regulation of lipid/glucose homeostasis, cellular metabolism, immunefunction and circadian rhythms, and have been implicated in thepathogenesis of several autoimmune, inflammatory and metabolic diseases(Burris et al. (2012) Chem. Biol., 19:51-59; Burris et al. (2013)Pharmacol. Rev., 65:710-778; Huh & Littman (2012) Eur. J. Immunol.,42:2232-2237; Jetten (2009) Nucl. Recept. Signal., 7:e003; Jetten et al.(2013) Front Endocrinol. (Lausanne), 4:1). Synthetic ligands have beendescribed that interact with the RORα and RORγ LBD functioning as aswitch that induces a ROR LBD conformational change. Such changepromotes the recruitment and displacement of regulatory coactivator andcorepressor proteins and upon ROR DBD binding to the ROR responsiveelement of the target genes lead to the induction or inhibition ofROR-regulated gene transcriptional activity. Therefore, small moleculedrugs that bind to the nuclear receptor LBDs such as ROR could elicit avariety of pharmacological responses, including activation (agonists),inactivation (antagonists or non-agonists), and for receptors that areconstitutively active, ligands can downregulate the constitutiveresponse (inverse agonists).

RORγt is the master regulator of human T Helper 17 (T_(H)17) celldifferentiation, function and cytokine production (Ivanov et al. (2006)Cell, 126:1121-1133). The critical role of T_(H)17 cells in thedevelopment or resolution of autoimmune, inflammatory, metabolic andoncologic diseases has been established and is conferred by itssignature proinflammatory cytokines IL-17A, IL-17F, IL-17AF, IL-21,IL-22 (Ghoreschi et al. (2010) Nature, 467:967-971; Kojetin & Burris(2014) Nat. Rev. Drug Discov., 13:197-216; Lee et al. (2012) Nat.Immunol., 13:991-999; Miossec et al. (2009) N. Engl. J. Med.,361:888-898; Miossec & Kolls (2012) Nat. Rev. Drug Discov., 11:763-776;Zepp et al. (2011) Trends Immunol., 32:232-239). In addition to T_(H)17cells, other sources of T_(H)17 cytokines include γ/δ T cells and innatelymphoid cells; however, T_(H)17 cells are distinguished by the specificregulation of RORγ and RORγt for cytokine transcriptional output andeffector functions, and also by RORα (Cua & Tato (2010) Nat. Rev.Immunol., 10:479-489; Huh & Littman (2012) Eur. J. Immunol.,42:2232-2237; Ivanov et al. (2006) Cell, 126:1121-1133; Spits & Di Santo(2011) Nat. Immunol., 12:21-27; Sutton et al. (2012) Eur. J. Immunol.,42:2221-2231; Yang et al. (2008) Immunity., 28:29-39). Also, in severalautoimmune disease models, there is a relative imbalance of increasedpathologic T_(H)17 cells over low numbers of protectiveimmunosuppressive CD4⁺CD25⁺Foxp3⁺ regulatory T cells [T_(Reg)] (Edwardset al. (2011) J. Neurol., 258:1518-1527; Littman & Rudensky (2010) Cell,140:845-858). Targeting RORα, RORγ and/or RORγt could have a broaderanti-inflammatory effect on the combined inhibition of all T_(H)17cytokine production and inflammatory cellular function, and in theinduction and expansion of suppressive T_(Reg) cells, important inautoimmune and inflammatory disease resolution, and may also havetherapeutic potential in metabolic diseases such as diet-induced insulinresistance known to be regulated by ROR. Since both RORγ1 and RORγtprotein isoforms, contain identical LBDs, small molecule RORγ modulatorsthat inhibit RORγt activity will also inhibit RORγ. Furthermore, RORαsimilarly plays an important regulatory role in the development orresolution of autoimmune and inflammatory disorders, and also inmetabolic and oncologic diseases (Kojetin & Burris (2014) Nat. Rev. DrugDiscov., 13:197-216). RORα critically regulates lipid and glucosehomeostasis and cellular metabolism that contribute to the developmentof metabolic diseases. Furthermore, RORα expression is downregulated inseveral types of cancer. Therefore, as ligand-dependent transcriptionfactors, it is desirable to prepare compounds that modulate RORα and/orRORγ activity which can be used in the treatment of RORα- and/orRORγ-regulated autoimmune, inflammatory, metabolic and oncologicdiseases.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula (I):

wherein:A is a monocyclic or bicyclic 5- to 8-membered heterocyclic ring havingone ring carbon replaced by N as shown, said ring optionally mono- orbi-substituted on one or more ring carbons independently with a C₁-C₆alkyl group;X is —(CH₂)_(n)—, —O—, or —NH—;Y is —(CH₂)_(p)—, —O—, —S— or —SO₂—, with the proviso that X and Y arenot both a heteroatom;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally mono- or bisubstituted independently with        halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy, -nitrile,        alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally mono- or bisubstituted independently with halogen,        alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O);        n is 0 or 1;        p is 0 or 1; and        q is 0, 1 or 2.

The present invention is also directed to compounds of the formula (I):

wherein:A is a monocyclic or bicyclic 5- to 8-membered heterocyclic ring havingone ring carbon replaced by N as shown, said ring optionally mono- orbi-substituted on one or more ring carbons independently with a C₁-C₆alkyl group;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally substituted with halogen, alkoxy, C₁-C₆        alkyl, —CN, -alkylsulfonyloxy, -nitrile, alkylsulfonyl,        halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally substituted with halogen, alkoxy, C₁-C₆ alkyl, —CN,        nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O); and        q is 0, 1 or 2.

The present invention is further directed to pharmaceutically acceptablesalts of the compounds of formula (I), pharmaceutical compositions andto methods of treating diseases and disorders. The compounds andcompositions disclosed herein are ROR modulators and useful for thetreatment of ROR-mediated diseases and disorders.

DETAILED DESCRIPTION

The invention is based in part on the discovery of ROR modulators, whichinteract with RORα and/or RORγ and thereby inhibit or induce RORα and/orRORγ activity, and RORα- and/or RORγ-regulated target gene and proteinexpression. The invention is also based on compositions comprising aneffective amount of a ROR modulator; and methods for treating orpreventing disorders regulated by RORα and/or RORγ, comprising theadministration of a therapeutically effective amount of a ROR modulator.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

The following definitions are used in connection with the RORmodulators:

“ROR” refers to RORα and/or RORγ isoforms.

“RORα” refers to all isoforms encoded by the RORA gene.

“RORγ” refers to all isoforms encoded by the RORC gene which includeRORγ1 and RORγt [RORγ2].

“RORα modulator” refers to a chemical compound that modulates, eitherdirectly or indirectly, the activity of RORα. RORα modulators includeantagonists/non-agonists, inverse agonists and agonists of RORα.

“RORγ modulator” refers to a chemical compound that modulates, eitherdirectly or indirectly, the activity of RORγ. RORγ modulators includeantagonists/non-agonists, inverse agonists and agonists of RORγ.

The term “ROR modulator” includes any and all possible isomers,stereoisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, hydrates, solvates, and prodrugs of the ROR modulatorsdescribed herein.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.

“C₁-C₃ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-3 carbon atoms. Examples of a C₁-C₃ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl and isopropyl.

“C₁-C₄ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-4 carbon atoms. Examples of a C₁-C₄ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl,isopropyl, isobutyl, sec-butyl and tert-butyl.

“C₁-C₅ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-5 carbon atoms. Examples of a C₁-C₅ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

“C₁-C₆ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-6 carbon atoms. Examples of a C₁-C₆ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, andneopentyl.

The term “cycloalkyl” refers to a cyclic hydrocarbon containing 3-6carbon atoms. Examples of a cycloalkyl group include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “heterocycle” as used herein refers to a cyclic hydrocarboncontaining 3-12 atoms wherein at least one of the atoms is an O, N, or Swherein a monocyclic heterocycle may contain up to two double bonds.Examples of heterocycles include, but are not limited to, aziridine,oxirane, thiirane, azetidine, oxetane, morpholine, thiomorpholine,thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine,dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.

The term “heteroaryl” as used herein refers to an aromatic mono- orpolycyclic radical of 5 to 12 atoms having at least one aromatic ringcontaining one, two, or three ring heteroatoms selected from N, O, andS, with the remaining ring atoms being C. Examples of heteroarylsinclude, but are not limited to, furan, thiophene, pyrrole, pyrroline,oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazineand triazene.

It is understood that any of the substitutable hydrogens on an alkyl,cycloalkyl, heterocycle and heteroaryl can be substituted independentlywith one or more substituents, for example 1, 2 or 3 substituents.Examples of substituents include, but are not limited to, halogen (e.g.,1, 2 or three halogens), C₁-C₃ alkyl, hydroxyl, alkoxy, oxo and cyanogroups.

A “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus monkey, and the terms “patient” and“subject” are used interchangeably herein.

The invention also includes pharmaceutical compositions comprising atherapeutically effective amount of a ROR modulator and apharmaceutically acceptable carrier. The invention includes a RORmodulator provided as a pharmaceutically acceptable prodrug, hydrate,salt, such as a pharmaceutically acceptable salt, enantiomers,stereoisomers, or mixtures thereof

Representative “pharmaceutically acceptable salts” include, e.g.,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

A “therapeutically effective amount” when used in connection with a RORmodulator is an amount effective for treating or preventing aROR-regulated disease or disorder.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body.

The term “treating”, with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject, or administering a prodrug derivative or analog of the compoundor pharmaceutically acceptable salt of the compound or composition tothe subject, which can form an equivalent amount of active compoundwithin the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to a RORmodulator.

The term “optionally substituted,” as used in this disclosure, means asuitable substituent can replace a hydrogen bound to a carbon, nitrogen,or oxygen. When a substituent is oxo (i.e., ═O) then 2 hydrogens on theatom are replaced by a single O. Suitable substituents are selected fromthe following which include, but are not limited to, hydroxyl, halogen,perfluorinated C₁-C₆ alkyl, amine, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkene,—C₂-C₁₂ alkyne, —(C₁-C₃ alkyl)-(cyclo alkyl), aryl, alkyl-aryl, —C(O)H,—C(O)OH, —C(O)alkyl, —C(O)—O-alkyl, —C(O)NH (alkyl), benzyl, —C(O)NH₂,—C(O)N(alkyl)₂, —NHC(O)H, —NHC(O)alkyl, —SO₂(alkyl), —SO₂NH₂,—SO₂NH(alkyl), —SO₂N(alkyl)₂, S, CN, and SCN. It will be understood bythose skilled in the art, with respect to any group containing one ormore substituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable. Furthermore,combinations of substituents and/or variables within any of the Formulaerepresented herein are permissible only if such combinations result instable compounds or useful synthetic intermediates wherein stableimplies a reasonable pharmologically relevant half-life at physiologicalconditions.

The following abbreviations are used herein and have the indicateddefinitions: ACTB is β-actin, AF-2 is activation function-2, AIBN isazobisisobutyronitrile, Boc and BOC are tert-butoxycarbonyl, Boc₂O isdi-tert-butyl dicarbonate, BOP is(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, BSA is bovine serum albumin, CD is cluster ofdifferentiation, CDI is 1,1′-carbonyldiimidazole, DBD is DNA-bindingdomain, DCC is N,N′-dicyclohexylcarbodiimide, DIEA and DIPEA isN,N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMEM isDulbecco's Modified Eagle Medium, DMF is N,N-dimethylformamide, DMSO isdimethyl sulfoxide, DOSS is sodium dioctyl sulfosuccinate, EC₅₀ is halfmaximal effective concentration, EDC and EDCI are1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ELISA isenzyme-linked immunosorbent assay, EtOAc is ethyl acetate, FBS is fetalbovine serum, FOXP3 is forkhead box P3, G-CSF is granulocytecolony-stimulating factor, h is hour, HATU is2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, HIV is human immunodeficiency virus, HOBt is1-Hydroxybenzotriazole, HPMC is hydroxypropyl methylcellulose, HPRT1 ishypoxanthine phosphoribosyltransferase 1, IC₅₀ is half maximalinhibitory concentration, IFN-γ is interferon gamma, IL is interleukin,IL-23R is interleukin 23 receptor, LAH is lithium aluminum hydride, LBDis ligand binding domain, MIQE is minimum information for publication ofquantitative real-time PCR experiments, MTBE is methyl tert-butyl ether,NBS is N-bromosuccinnide, NMP is N-methyl-2-pyrrolidone, oxone ispotassium peroxymonosulfate, PBMCs is peripheral blood mononuclearcells, PCR is polymerase chain reaction, Pd/C is palladium on carbon,PGK1 is phosphoglycerate kinase, PPIA is peptidylprolyl isomerase A,REST is Relative Expression Software Tool, RORα is retinoic acidreceptor-related orphan receptor alpha, RORγ is retinoic acidreceptor-related orphan receptor gamma, TBAB is tetrabutylammoniumbromide, TBP is terminal binding protein, TFA is trifluoroacetic acid,TFRC is transferrin receptor, TGF-β1 is transforming growth factor beta1, T_(H)17 is T helper 17 cell, TGPS is tocopherol propylene glycolsuccinate, THF is tetrohydrofuran, TLC is thin layer chromatography,TR-FRET is time-resolved fluorescence resonance energy transfer and μMis micromolar.

In one embodiment of the present invention, provided is a compound offormula (I):

wherein:A is a monocyclic or bicyclic 5- to 8-membered heterocyclic ring havingone ring carbon replaced by N as shown, said ring optionally mono- orbi-substituted on one or more ring carbons independently with a C₁-C₆alkyl group;X is —(CH₂)_(n)—, —O—, or —NH—;Y is —(CH₂)_(p)—, —O—, or —S—, with the proviso that X and Y are notboth a heteroatom;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally mono- or bisubstituted independently with        halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy, -nitrile,        alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally mono- or bisubstituted independently with halogen,        alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O);        n is 0 or 1;        p is 0 or 1; and        q is 0, 1 or 2,        or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, provided is a compoundof formula (I), wherein A is unsubstituted piperidinyl, pyrrolidinyl,[2,2,1]bicycloazepinyl or azepanyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein A is piperidinyl, pyrrolidinyl or azepanyl mono-or bi-substituted independently with a C₁-C₆ alkyl group.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein A is piperidinyl, pyrrolidinyl or azepanylmono-substituted with methyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein A is piperidinyl, pyrrolidinyl or azepanylbi-substituted with methyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein X is —CH₂—, —O—, or —NH—.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein Y is —O—.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is —C₁-C₆ alkyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is methyl, ethyl, propyl or t-butyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is unsubstituted phenyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is phenyl substituted with halogen,alkylsulfonyl, alkoxy or C₁-C₆ alkyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is cycloalkyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₁ is an unsubstituted 5- or 6-memberedheteroaryl group having one or more ring carbons replaced by N.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₂ is an unsubstituted 5- to 7-memberedheteroaryl group having one, two or three ring carbons replaced by N.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₂ is unsubstituted pyrazolyl or triazolyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₂ is unsubstituted pyrazolyl.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein R₂ is linked via a carbon atom.

In another embodiment of the present invention, provided is a compoundhaving the formula (Ia):

wherein:X is —(CH₂)_(n)—, —O—, or —NH—;Y is —(CH₂)_(p)—, —O—, or —S—, with the proviso that X and Y are notboth a heteroatom;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally mono- or bisubstituted independently with        halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy, -nitrile,        alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally mono- or bisubstituted independently with halogen,        alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O);        R₃, R₄, R₅ and R₆ are, independently of each other, H or —C₁-C₆        alkyl;        n is 0 or 1;        p is 0 or 1; and        q is 0 1 or 2,        or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, provided is a compound,having the formula (Ib):

wherein:X is —(CH₂)_(n)—, —O—, or —NH;Y is —(CH₂)_(p)—, —O—, or —S—, with the proviso that X and Y are notboth a heteroatom;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally mono- or bisubstituted independently with        halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy, -nitrile,        alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally mono- or bisubstituted independently with halogen,        alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O);        R₃ and R₄ are, independently of each other, H or —C₁-C₆ alkyl;        n is 0 or 1;        p is 0 or 1; and        q is 0, 1 or 2,        or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, provided is a compoundhaving the formula (Ic):

wherein:X is —(CH₂)_(n)—, —O—, or —NH;Y is —(CH₂)_(p)—, —O—, or —S—, with the proviso that X and Y are notboth a heteroatom;Z is —(CH₂)_(q)—;R₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally mono- or bisubstituted independently with        halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy, -nitrile,        alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally mono- or bisubstituted independently with halogen,        alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O);        R₃, R₄, R₅ and R₆ are, independently of each other, H or —C₁-C₆        alkyl;        n is 0 or 1;        p is 0 or 1; and        q is 0, 1 or 2,        or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, provided is a compoundof formula (I), wherein said compound is:

-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-cyclohexylethanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-phenylethanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-4-phenylbutan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-3-phenylpropan-1-one,-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one    or-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one.

In another embodiment of the present invention, provided is a compoundof formula (I), wherein said compound is:

-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)phenylmethanone,-   (3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)(phenyl)methanone,-   1-(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(phenyl)methanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2-phenylethanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(cyclopentyl)methanone,-   (3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)(cyclohexyl)methanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2,2-dimethylpropan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-2-phenylethanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(phenyl)methanone,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-3-phenylpropan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-2-phenylethanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(cyclopentyl)methanone,-   (2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(phenyl)methanone,-   1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylethanone,-   1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-3-phenylpropan-1-one    or-   1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2,2-dimethylpropan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2-fluorophenyl)propan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(4-fluorophenyl)propan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(3-fluorophenyl)propan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,4-difluorophenyl)propan-1-one,-   1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(p-tolyl)propan-1-one,-   4-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile,-   3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2-fluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(4-fluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,3-difluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,4-difluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(p-tolyl)methanone,-   4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile,-   3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(3-fluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(4-fluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-fluorophenyl)methanone.-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2-fluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2,3-difluorophenyl)methanone,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(p-tolyl)methanone,-   4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-methoxyphenyl)methanone,-   3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidine-1-carbonyl)benzonitrile,-   (4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(m-tolyl)methanone,-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one,-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one,-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one,-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,-   rac.-trans-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrile,-   rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one,-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one,-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one,-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one,-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,-   rac.-cis-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrile    or-   rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one.

In another embodiment of the present invention, provided is a compoundof formula (II):

wherein:A is a monocyclic or bicyclic 5- to 8-membered heterocyclic ring havingone ring carbon replaced by N as shown, said ring optionally mono- orbi-substituted on one or more ring carbons independently with a C₁-C₆alkyl group;Z is —(CH₂)_(q)—;Y is —(CH₂)_(p)— or OR₁ is —C₁-C₆ alkyl, optionally substituted with one or more —OH, halogenor —CN,

-   -   phenyl, optionally substituted with halogen, alkoxy, C₁-C₆        alkyl, —CN, -alkylsulfonyloxy, alkylsulfonyl, halo-C₁-C₆ alkyl        or C₁-C₅ cycloalkyl,    -   cycloalkyl, optionally substituted,    -   heterocycle, optionally substituted or    -   a 5- or 6-membered heteroaryl group having one or more ring        carbons independently replaced by N, O or S, said heteroaryl        optionally substituted with halogen, alkoxy, C₁-C₆ alkyl, —CN,        nitrile or perfluorinated C₁-C₆ alkyl;        R₂ is a 5- to 7-membered heteroaryl group having one, two or        three ring carbons independently replaced by N, O or S, said        heteroaryl optionally mono- or bi-substituted independently with        C₁-C₆ alkyl, —CN or (═O); and        q is 0, 1 or 2,        p is 0 or 1,        or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein A is unsubstituted piperidinyl, pyrrolidinyl,[2,2,1]bicycloazepinyl or azepanyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein A is piperidinyl, pyrrolidinyl or azepanylmono- or bi-substituted independently with a C₁-C₆ alkyl group.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein A is piperidinyl, pyrrolidinyl or azepanylmono-substituted with methyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein A is piperidinyl, pyrrolidinyl or azepanylbi-substituted with methyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is —C₁-C₆ alkyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is methyl, ethyl, propyl or t-butyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is unsubstituted phenyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is phenyl substituted with halogen,alkylsulfonyl, alkoxy, —CN, alkyl, or C₁-C₆ alkyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is cycloalkyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₁ is an unsubstituted 5- or 6-memberedheteroaryl group having one or more ring carbons replaced by N.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₂ is an unsubstituted 5- to 7-memberedheteroaryl group having one, two or three ring carbons replaced by N.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₂ is unsubstituted pyrazolyl or triazolyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₂ is unsubstituted pyrazolyl.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein R₂ is linked via a carbon atom.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein said compound is:

-   1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-ylsulfonyl)benzonitrile,-   5-(1H-pyrazol-4-yl)-1-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-1H-indazole,-   1-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole    or-   1-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole.

In another embodiment of the present invention, provided is a compoundof formula (II), wherein said compound is:

-   5-(1H-pyrazol-4-yl)-1-((1-tosylpiperidin-4-yl)methyl)-1H-indazole,-   3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)sulfonyl)benzonitrile,-   1-((1-((4-(difluoromethyl)phenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-(((3R,5S)-5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-trans-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile,-   rac.-trans-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-(((3R,5S)-5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   rac.-cis-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile,-   rac.-cis-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((4-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((3-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((2-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((1-((2,3-difluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((5,5-dimethyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   1-((5,5-dimethyl-1-(m-tolylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,-   3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrile,-   4-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrile    or-   1-((1-((4-fluoro-3-methylphenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole.

Certain compounds of the present invention of formula (I) are furtherexemplified by structure as follows:

Certain compounds of the present invention of formula (II) are furtherexemplified by structure as follows:

In another embodiment, provided is a pharmaceutical composition,comprising a therapeutically effective amount of a compound according toformulas (I) or (II), or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

In another embodiment, provided is a method of treating a Retinoic AcidReceptor-Related Orphan Receptor mediated disease or disorder,comprising the step of administering a therapeutically effective amountof a compound according to formulas (I) or (II), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

In another embodiment, provided is a method of treating a Retinoic AcidReceptor-Related Orphan Receptor mediated disease or disorder,comprising the step of administering a therapeutically effective amountof a compound according to formulas (I) or (II) to a patient in needthereof, wherein said disease or disorder is an autoimmune,inflammatory, metabolic or oncologic disease or disorder.

In another embodiment, provided is a method of treating a Retinoic AcidReceptor-Related Orphan Receptor mediated disease or disorder,comprising the step of administering a therapeutically effective amountof a compound according to formulas (I) or (II) to a patient in needthereof, wherein said disease or disorder is rheumatoid arthritis,psoriasis, psoriatic arthritis, polymyalgia rheumatica, multiplesclerosis, lupus, uveitis, inflammatory bowel disease, ankylosingspondylitis, vasculitis, atherosclerosis, macular degeneration,diabetes, obesity, cancer, asthma or chronic obstructive pulmonarydisease.

In another aspect, methods of inhibiting, preventing or treating adisease, or symptoms of a disease, regulated by RORα and/or RORγ, isprovided, which comprises administering to a subject in need thereof, atherapeutically-effective amount of a ROR modulator. In someembodiments, the disease regulated by RORα and/or RORγ is selected fromAutoimmune, Inflammatory, Metabolic and Oncologic Diseases, includingbut not limited to angina pectoris, myocardial infarction,atherosclerosis, cystic fibrosis, gastritis, autoimmune myositis, giantcell arteritis, Wegener's granulomatosis, asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, juvenile rheumatoid arthritis,allergen-induced lung inflammation, allergy, psoriasis, psoriaticarthritis, colitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, Sjogren's syndrome, dry eye, optic neuritis,neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, Gravesdisease, multiple sclerosis, autoimmune uveitis, ankylosing spondylitis,organ transplant rejection, polymyalgia rheumatic, systemic lupuserythematosus, cutaneous lupus, lupus nephritis, glomerulonephritis,diabetes mellitus type 1, pulmonary inflammation, macular degeneration,obesity, non-alcoholic fatty liver disease, steatohepatitis, insulinresistance, diabetes mellitus type 2, glucose intolerance, and metabolicsyndrome; and primary and metastatic Oncologic Diseases, including butnot limited to multiple myeloma, bone disease associated with multiplemyeloma, lymphoma, melanoma, sarcoma, colorectal cancer, esophagealcancer, and cancers of the bladder, brain, breast, cervix, ovaries, headand neck, kidney, liver, lung, prostate and pancreas.

Also described are methods of modulating RORα and/or RORγ activity as anagonist, inverse agonist or antagonist/non-agonist in a subject, whichcomprises administering to a subject in need thereof a pharmaceuticallyeffective amount of a ROR modulator.

Also described are methods of inducing or inhibiting RORα- and/orRORγ-regulated target gene expression and protein production in asubject which comprises administering to a subject in need thereof apharmaceutically effective amount of a ROR modulator.

Also described are methods of regulating corepressor and/or coactivatorprotein interaction with RORα and/or RORγ LBD in a subject thatcomprises administering to a subject in need thereof a pharmaceuticallyeffective amount of a ROR modulator.

Also described are methods of decreasing or increasing the amount ofRORα- and/or RORγ-regulated production of T_(H)17 cytokines IL-17A,IL-17F, IL-17AF, IL-21, and/or IL-22 in a subject which comprisesadministering to a subject in need thereof a pharmaceutically effectiveamount of a ROR modulator.

Also described are methods of inducing or inhibiting, either directly orindirectly, RORα- and/or RORγ-regulated cell proliferation or activationin a subject which comprises administering to a subject in need thereofa pharmaceutically effective amount of a ROR modulator.

The ROR modulators can each be administered in amounts that aresufficient to treat or prevent but are not limited to Autoimmune,Inflammatory, Metabolic and Oncologic Diseases, or prevent thedevelopment thereof in subjects.

The invention also includes pharmaceutical compositions useful fortreating or preventing a ROR regulated disease, or for inhibiting a RORregulated disease, or more than one of these activities. Thecompositions can be suitable for internal use and comprise an effectiveamount of a ROR modulator and a pharmaceutically acceptable carrier. TheROR modulators are especially useful in that they demonstrate very lowsystemic toxicity or no systemic toxicity.

Administration of the ROR modulators can be accomplished via any mode ofadministration for therapeutic agents. These modes include systemic orlocal administration such as oral, nasal, parenteral (intravenous),intramuscular, intrathecal, intra-vitreal, transdermal, subcutaneous,vaginal, buccal, rectal, topical administration modes or as adrug-eluting stent.

Depending on the intended mode of administration, the compositions canbe in solid, semi-solid or liquid dosage form, such as, for example,injectables, tablets, suppositories, pills, time-release capsules,elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, orthe like, sometimes in unit dosages and consistent with conventionalpharmaceutical practices. Likewise, they can also be administered inintravenous (both bolus and infusion), intraperitoneal, intrathecal,intra-vitreal injection, subcutaneous or intramuscular form, all usingforms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a ROR modulator and a pharmaceutically acceptablecarrier, such as: a) a diluent, e.g., purified water, triglyceride oils,such as hydrogenated or partially hydrogenated vegetable oil, ormixtures thereof, corn oil, olive oil, sunflower oil, safflower oil,fish oils, such as EPA or DHA, or their esters or triglycerides ormixtures thereof, omega-3 fatty acids or derivatives thereof, lactose,dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin,glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearicacid, its magnesium or calcium salt, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chlorideand/or polyethylene glycol; for tablets also; c) a binder, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, magnesium carbonate,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth or sodium alginate, waxesand/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g.,starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acidor its sodium salt, or effervescent mixtures; e) absorbent, colorant,flavorant and sweetener; f) an emulsifier or dispersing agent, such asTween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol,transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin ETGPS or other acceptable emulsifier; and/or g) an agent that enhancesabsorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the ROR modulatoris dissolved in or mixed with a pharmaceutically acceptable solvent suchas, for example, water, saline, aqueous dextrose, glycerol, ethanol, andthe like, to thereby form an injectable isotonic solution or suspension.Proteins such as albumin, chylomicron particles, or serum proteins canbe used to solubilize the ROR modulators.

The ROR modulators can be also formulated as a suppository that can beprepared from fatty emulsions or suspensions; using polyalkylene glycolssuch as propylene glycol, as the carrier.

In further embodiments, the pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,aerosols, solid dosage forms, powders, immediate release formulations,controlled release formulations, fast melt formulations, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations

The ROR modulators can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564, thecontents of which are herein incorporated by reference in theirentirety.

ROR modulators can also be delivered by the use of monoclonal antibodiesas individual carriers to which the ROR modulators are coupled. The RORmodulators can also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the ROR modulators canbe coupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, ROR modulators are notcovalently bound to a polymer, e.g., a polycarboxylic acid polymer, or apolyacrylate.

Parenteral injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 80%,from about 5% to about 60%, or from about 1% to about 20% of the RORmodulator by weight or volume.

The dosage regimen utilizing the ROR modulator is selected in accordancewith a variety of factors including type, species, age, weight, sex,race, diet, and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular ROR modulatoremployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the present invention, when used for theindicated effects, range from about 0.1 mg to about 5000 mg of theactive ingredient per unit dose which could be administered. In oneembodiment, the compositions are in the form of a tablet that can bescored. Appropriate dosages of the ROR modulators can be determined asset forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis ofTherapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226, thecontents of which are hereby incorporated by reference.

ROR modulators can be administered in a single daily dose, or the totaldaily dosage can be administered in divided doses of two, three or fourtimes daily. Furthermore, ROR modulators can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration can becontinuous rather than intermittent throughout the dosage regimen. Otherillustrative topical preparations include creams, ointments, lotions,aerosol sprays and gels, wherein the concentration of the ROR modulatorranges from about 0.1% to about 15%, w/w or w/v.

The ROR modulators can also each be administered in amounts that aresufficient to treat or prevent ROR-associated diseases. These diseasesinclude, but are not limited to, Autoimmune, Inflammatory, Metabolic andOncologic diseases, either individually or in combination with one ormore agents and or methods for treating and preventing theseROR-regulated diseases.

General Schemes Methods for Making the RORα, RORγ and RORα/RORγModulators

Compounds of the present invention can be prepared beginning withcommercially available starting materials and utilizing generalsynthetic techniques and procedures known to those skilled in the art.Chemicals may be purchased from companies such as for exampleSigmaAldrich, Argonaut Technologies, VWR and Lancaster. Chromatographysupplies and equipment may be purchased from such companies as forexample AnaLogix, Inc, Burlington, Wis.; Biotage AB, Charlottesville,Va.; Analytical Sales and Services, Inc., Pompton Plains, N.J.; TeledyneIsco, Lincoln, Nebr.; VWR International, Bridgeport, N.J.; Varian Inc.,Palo Alto, Calif., and Mettler Toledo Instrument Newark, Del. Biotage,ISCO and Analogix columns are pre-packed silica gel columns used instandard chromatography.

Examples of synthetic pathways useful for making ROR modulators of thepresent invention are set forth in the Examples below and generalized inSchemes 1-4 below.

The starting materials I shown in scheme 1 wherein X is a group capableof participating in a transition metal catalyzed cross couplingreaction, such as a chloride, bromide, iodide or triflate, arecommercially available or readily prepared from commercially availablecompounds. Alkylation of I on nitrogen with a compound II in which B isa leaving group such as a bromide, chloride or tosylate and Y is eithera protecting group, an acyl group of the invention or an acyl groupwhich can be transformed into an acyl group, of the invention to give acompound III can be accomplished by standard methods, such as treatmentof a solution of compound I in suitable inert solvent such as DMF withbase such as NaH followed by compound II. The reaction may be carriedout at room temperature, or at a mildly elevated temperature. Thisreaction may give a mixture of 1- and 2-alkylated products. These can beseparated chromatography or carried on and separated at a later stage asconvenient.

The resulting III may then be coupled to the heteroaromatic derivativesHet-W (IV) in which Het is an optionally substituted 5-7-memberedheteroaromatic compound, which may incorporate a protecting group asappropriate, and W is a functional group such as a boronic acid or ahalogen atom, capable of participating in a transition metal catalyzedcross-coupling reaction such as a Suzuki reaction. Skilled organicchemists will understand how to select the particular choice of X, W andtransition metal catalyst for a given desired transformation andincorporate the appropriate protection/deprotection methods, whereneeded. In some cases, it may be desirable to convert X to a metalderivative prior to coupling. For example, see Stadlwieser, J. F., etal, Helvetica Chimica ACTA 2006, 89, 936-946. This is typically doneusing a bisborane such as bis(pinacolato)diboron in the presence of asuitable catalyst such as PdCl₂(dppf)DCM to give a boronic acidderivative prior to the coupling reaction with Het-W. See for example:N. Kudo et al., Angew. Chem. Int. Ed., 2006, 45, 1282-1284 and Dvorak,C. A.; et al., Journal of Organic Chemistry 2005, 70, 4188-4190; Barder,T. E., et al. J. Am. Chem. Soc. 2005, 127, 4685-4696, Isley, N. W. etal, Journal of the American Chemical Society, 2013, 135, 17707-17710. Insome cases, other metalling reagents leading for example toorganostannane or organozinc intermediates may be preferable for aparticular desired coupling reaction. For a recent review on theimplementation of organo zinc mediated coupling reactions, see Sidduri,A., et al., Synthesis 2014, 46, 430-444.

Carrying out the coupling reaction will then lead to the targetcompounds V, which depending on the selection of Y, may be compounds ofthe invention or intermediates that can be converted to compounds of theinvention. For example, in cases where Y is an acyl group of theinvention or a protected variant of such, removal of any protectinggroups will lead directly to compounds of the invention. In cases whereY is a protecting group, for example a benzyl, carboxybenzyl or Bocgroup, removal using the appropriate conditions, well known to medicinalchemists, would lead to VI, which can be transformed to a compound ofthe invention via acylation, followed by any needed functional group orprotecting group manipulation.

In some cases, it may be desirable to manipulate the group Y instructure III to give VII in which Y′ is an acyl group of the inventionor may be simply transformed into an acyl group of the invention byroutine transformations, prior to coupling the heterocyclic ring giveVIII.

Alternatively, heterocycles Het in the above structures may beconstructed directly attached to the indazole ring. Such transformationsare well known in heterocyclic chemistry and skilled medicinal chemistswill understand how to vary the order of the steps to suit theparticular choice of target structure. For example, as shown in Scheme2, 1,2,3-triazoles may be ready constructed by first converting acompound of structure III to an acetylene for example by treatment withTMS-acetylene in the presence of a suitable transition metal catalyst.Typically the TMS group is lost during workup and when it is stillpresent, it can be removed under standard basic conditions to give acompound of structure IX. Treatment of IX with a substituted azidederivative in the presence of a suitable catalyst, for example, a coppercatalyst then gives the corresponding triazole of formula X which iseither a compound of the invention or readily converted to a compound ofthe invention following suitable functional group transformations.Triazole formation using this method is widely used in organic chemistryand is typically referred to as “click chemistry”. One variant isdescribed in, Tornoe, C. W., et al, J. Org Chem, 2002, 67, 3057-3064.The application of click chemistry to the synthesis of certain electrondeficient triazoles is described in Chattopadhysy, B., Organic Letters2010, 12, 2166-2169. Depending on the choice of R₃, furtherfunctionalization of this substituent can be carried out after triazoleformation using standard methods.

Alternative sequences are also envisioned, in which X of III is anitrile or can be converted to a nitrile. Subsequent reactions leadingto 1,2,4-triazoles, oxadiazoles and tetrazoles can be carried followedestablished literature precedent.

In some cases, it may be desirable to construct the heteroaromaticspecies from a carbonyl derivative such as XI, Y═H, OH, NHR₄, or OR₅,wherein R₄ is H, lower alkyl or OR₆, wherein R₆ is H or lower alkyl andR₅ is lower alkyl or another substituent suitable for the displacementchemistry associated with the intended heterocycle construction. Suchintermediates can be alkylated as above with the appropriate reagents ofstructure II to give compounds of structure XII as described in Scheme1, followed by elaboration of the carbonyl derivative to the desiredheterocyclic derivatives, XIII using the chemistry appropriate to thetarget heterocycle. In general, the sequence of steps necessary to carryout these transformations is well established in the chemistryliterature. The sequence of the steps may be altered to suit theparticular selection of target, available starting materials andexperimental convenience. 1,2,4-Oxadiazoles and 1,2,4-triazoles areamong the types of heterocycles available through this chemistry. Theorder of the steps may be varied to suit the particular target andefficiency of the various steps involved.

The intermediate compounds II, are either commercially available or canbe prepared in a few steps using standard techniques well known topracticing medicinal chemists. The choice of protecting group willdepend on the remaining steps anticipated during the rest of thesynthesis of the particular target compound. Typically, benzyl-,carboxybenzyloxy- or Boc groups are used. A particularly useful guide toselection of nitrogen protecting groups is Greene's Protective Groups inOrganic Synthesis by Peter G. M. Wuts and T. W. Greene, 4^(th) ed.,Wiley, 2007.

Compounds II bearing alkyl groups are also available through purchase ora series of simple synthetic steps. For example, Boc-protected2-methyl-4-hydroxymethyl piperidine is commercially available, forexample from Affinity Research Chemicals of Richmond, Del. or viasynthesis using the method described in WO03103669.4-Hydroxymethyl-2,2,6,6-tetramethylpiperidine can be prepared using themethod described in WO2012068589 (U.S. application Ser. No. 13/988,180)and 2,6-dimethyl-4-hydroxymethylpiperidine can be prepared as describedin US20090042900. These various intermediates can be protected andfunctionalized through a series of routine steps for use in theprocedures outlined in the above schemes. 5-Methyl- and5,5-dimethylpyrrolidine derivatives can be prepared from thecorresponding pyrrolidinones as shown in Scheme 4 and the examplesreported herein.

Thus, as shown in Scheme 4, a compound of structure XIV in which one ofR₆ and R₇ is lower alkyl and the other is H or lower alkyl can bealkylated on nitrogen, for example with benzylbromide in the presence ofa suitable base, for example NaH in DMF at 0° C. to give a compound ofstructure XV. Treatment of XV with a dialkylcarbonate, such as dimethylcarbonate in the presence of a strong base, for example lithiumdiisopropylamide at a temperature between −78° C. and room temperaturein a suitable inert solvent such as THF leads to the corresponding alkylester of structure XVI. Reduction of XVI with a strong reducing agentsuch as lithium aluminum hydride at a temperature of 0° C. to roomtemperature in a suitable solvent such as THF leads to an alcohol ofstructure XVII in which the hydroxyl moiety can be converted into aleaving group, for example by treatment with tosyl chloride in thepresent of a suitable base, for example triethylamine in dichloromethaneto give a compound such as XVIII, which is suitable for use in thealkylation reaction described in Scheme 1. The alcohol XVII could alsobe converted into other leaving groups such as a halogen if use of atosyl group is not desired.

Intermediate bicyclic compounds II, can be prepared in a few steps usingstandard techniques well known to practicing medicinal chemists.Convenient starting materials include aza-bicyclic alcohols and ketoneswhich can be homologated, for example via a Wittig reaction to aaldehyde or carboxylate which after reduction, will yield ahydroxymethyl azabicyclic derivative that in turn can be transformed toa bicyclic compound of formula II. Some references to these startingmaterials include: EP978,280, EP115,933, U.S. Pat. No. 4,013,668, Krow,G., et al., Synthetic Communications 1972, 2, 211-214, Gong, L., et al.Bioorg Med Chem Lett 2003, 13, 3587-3600. The choice of protecting groupwill depend on the remaining steps anticipated during the rest of thesynthesis of the particular target compound. Typically, benzyl-,carboxybenzyloxy- or Boc groups are used.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims. Thestructures of the examples were converted into a name using ChemDrawUltra by PerkinElmer Informatics.

Preparative purification by HPLC was carried out on a Waters 2707 AutoPurification system equipped with a 2996 PDA detector and using aX-Bridge C18, 150×30 mm ID, 5μ column; mobile phase A: 0.01M aqueousammonium acetate, mobile phase B: acetonitrile. The gradient programwas: Time (min)/% of B: 0/30, 3/30, 20/80, 25/90 and a total run time of30 min. Detection was set at 210 nm.

Proton NMR was run on an Aligent 400MRDD2 400 MHz instrument. Analyticalpurity was determined on a Waters Acquity UPLC system with 2998 PDAdetector using a Acquity BEH C18, 100×2.1 mm, 1.7μ column. Method 1employed a mobile phase A of 0.025% aqueous TFA; mobile phase B of0.025% TFA in acetonitrile and method B employed a mobile phase A of0.25% aqueous formic acid; mobile phase B of 0.025% formic acid inacetonitrile. Run times were 6 min with the gradients determined bycompound polarity; the detection range was 200 to 400 nm.

LC-MS were determined using one of two systems. Method-1 used a WatersAcquity UPLC system with 2998 PDA detector. Column: Acquity; BEH; C18,50×2.1 mm; 1.7μ; mobile phase A: 0.025% aqueous formic acid; mobilephase B: 0.025% formic acid in acetonitrile. The gradient program variedbased on compound polarity over a 5 min run time and a detection rangeof 200 nm to 400 nm was employed. Method-2 used a Waters Alliance 2695HPLC system with 2998 PDA detector. Column: X-Bridge C18, 50×4.6 mm,2.5μ; mobile phase A: 0.01M aqueous ammonium bicarbonate; mobile phaseB: acetonitrile. The run time was 7 min and the gradient variedaccording to compound polarity; a detection range of 200-400 nm wasemployed. The MS detector was a Waters Single Quadra pole Mass Detector,model SQD-2 with Z-spray technique equipped with an ESI source employingboth ‘Positive’ and ‘Negative’ scan modes.

Intermediate 1 Synthesis of1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step 1

A mixture of 4-bromo-1H-pyrazole (150 g, 1.02 mol, 1.0 eq),3,4-dihydro-2H-pyran (128 g, 1.50 mol, 1.5 eq) and trifluoroacetic acid(7.8 mL, 0.10 mol, 0.1 eq) was stirred at 80° C. for 16 h. Progress ofthe reaction was monitored by TLC (10% ethyl acetate-hexane R_(f)=0.4).After completion of the reaction, the reaction mixture was diluted withethyl acetate and was washed with saturated aqueous sodium bicarbonateand brine. The organic layer was dried over anhydrous sodium sulfate,filtered and the solvents were evaporated under reduced pressure toobtain 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (180 g, 76%) asa brown oil. LCMS purity: 81.4%; (ES⁺): m/z 231.2 (M+H⁺); tr=1.88 min.

Step 2

Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to asolution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g,0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature.

Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and thereaction flask was purged with argon for 20 min. PdCl₂(dppf)DCM (26.0 g,31.8 mmol, 0.05 eq) was added and the mixture was purged with argon forfurther 10 min followed by stirring at 80° C. for 12 h. After completionof the reaction (monitored by TLC, 10% ethyl acetate-hexane, R_(f)=0.3),the mixture was cooled to room temperature and filtered through a bed ofdiatomaceous earth washing with ethyl acetate and the combined organiclayers were evaporated under reduced pressure to give1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(280 g crude) as a brown oil. LCMS purity: 57.8%; (ES⁺): m/z 279.18(M+H⁺); tr=1.95 min. The compound was used without further purification.

Intermediate 2 Synthesis of benzyl3-(tosyloxymethyl)pyrrolidine-1-carboxylate

To a solution of benzyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (7.50g, 31.9 mmol, 1.0 eq) and triethylamine (13 mL, 95.7 mmol, 3.0 eq) indichloromethane (70 mL) was added TsCl (9.12 g, 47.8 mmol, 1.5 eq)slowly at 0° C. The mixture was allowed to room temperature and wasstirred overnight. After completion of the reaction (monitored by TLC,50% ethyl acetate-hexane R_(f)=0.6), the mixture was poured into coolwater and washed with water followed by brine. The organic layer wasdried over anhydrous sodium sulfate and solvent was removed underreduced pressure. The crude product was purified by columnchromatography over neutral alumina, eluting with a 0-12% gradient ofethyl acetate in hexanes to afford benzyl3-(tosyloxymethyl)pyrrolidine-1-carboxylate (8.16 g, 68%) as acolourless oil. LCMS m/z=390 (M+1.

Intermediate 3 Synthesis of 1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate

Reaction step 1. Synthesis of 1-benzyl-5-methylpyrrolidin-2-one

To a solution of 5-methylpyrrolidin-2-one (15 g, 152 mmol, 1.0 eq) inDMF (115 mL), was slowly added NaH (5.4 g, 230 mmol, 1.5 eq) followed bybenzyl bromide (21.7 mL, 182 mmol, 1.2 eq) at 0° C. and the reactionmixture was allowed to warm to room temperature over 3 h. Aftercompletion of reaction (monitored by TLC, 20% ethyl acetate-hexane,KMnO₄, R_(f)=0.45), the reaction was quenched by the addition of icecubes and was extracted with ethyl acetate (500 mL). The organic extractwas dried over anhydrous sodium sulfate and the solvent removed underreduced pressure. The crude product was purified by columnchromatography on silica gel (100-200 mesh), eluting with 10% ethylacetate in hexanes to afford 25 g of 1-benzyl-5-methylpyrrolidin-2-oneas oil. LC-MS (ES⁺) m/z: 190.1 (M+1); purity=92.5%.

Reaction step 2. Synthesis of methyl1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylate

To a solution of diisopropyl amine (7.84 mL, 55.5 mmol, 2.1 eq) in THF(50 mL), at −78° C. was slowly added n-BuLi (2.5 M in hexanes) (21.5 mL,52.8 mmol, 2.0 eq) and the mixture was allowed to warm to −20° C. for 40min. A solution of 1-benzyl-5-methylpyrrolidin-2-one (5.0 g, 26 mmol,1.0 eq) in THF was added to the above reaction mixture at −78° C. andthe mixture was stirred for 45 min. Then dimethyl carbonate (4.45 mL,52.8 mmol, 2.0 eq) was added at −78° C. and the mixture was allowed towarm to room temperature slowly over 5 h. After completion of thereaction (monitored by TLC, 30% ethyl acetate-hexane, KMnO₄,R_(f)=0.65), the reaction was quenched by the slow addition of 1M HCl at0° C. and was extracted with ethyl acetate (300 mL). The organic extractwas dried over anhydrous sodium sulfate and the solvents were removedunder reduced pressure to afford 2.1 g of methyl1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylate as a sticky foam. LC-MS(ES⁺) m/z: 248.1 (M+1); purity=92% (mixture of isomers).

Reaction step 3. Synthesis of (1-benzyl-5-methylpyrrolidin-3-yl)methanol

Lithium Aluminium hydride (2M in hexane, 15.7 mL, 31.5 mmol, 3.7 eq) wasadded slowly to a solution of methyl1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylate (2.1 g, 8.20 mmol, 1.0eq) in THF (35 mL), at 0° C. and the mixture was allowed to warm to roomtemperature over 3 h. After completion of the reaction (monitored byTLC, 30% ethyl acetate-hexane, KMnO₄, R_(f)=0.45), the reaction wasquenched by slow addition of 1.25 mL of water and 1.25 mL of 15% NaOHsolution followed by 3.75 mL of water at 0° C. The reaction mixture wasfiltered through a small bed of celite and the filtrate was concentratedunder reduced pressure to afford 1.7 g (crude) of(1-benzyl-5-methylpyrrolidin-3-yl) methanol as sticky foam. LC-MS (ES⁺)m/z: 206.1 (M+1); purity=80% (mixture of isomers).

Reaction step 4. Synthesis of (1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate

To a solution of (1-benzyl-5-methylpyrrolidin-3-yl) methanol (1.7 g, 8.3mmol, 1.0 eq) in dichloromethane (25 mL), triethylamine (3.47 mL, 24.9mmol, 3.0 eq) was added, followed by tosyl chloride (1.89 g, 10 mmol,1.2 eq) at 0° C. The reaction mixture was allowed to warm to roomtemperature and was stirred for 12 h. After completion of the reaction(monitored by TLC, 50% ethyl acetate-hexane, R_(f)=0.65), the reactionmixture was quenched by addition of NaHCO₃ solution (25 mL) and wasextracted with dichloromethane. The combined extracts were washed withbrine solution. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford 0.92 g (31%)of (1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate asa sticky solid. LC-MS (ES⁺) m/z: 360.16 (M+1); purity=75%.

Intermediate 4 Benzyl 4-((tosyloxy)methyl)azepane-1-carboxylate

Reaction step 1. Synthesis of 1-benzyl 4-ethyl5-oxoazepane-1,4-dicarboxylate

Ethyl diazoacetate (12.7 mL, 112 mmol, 1.3 eq) was added to a solutionof benzyl 4-oxopiperidine-1-carboxylate (20.0 g, 85.8 mmol, 1.0 eq) indiethyl ether (200 mL) at −78° C. followed by and BF₃.OEt₂ (4.4 mL, 86mmol, 1.0 eq). The reaction mixture was stirred at −78° C. for 1 h thenallowed to attain to room temperature to give a clear solution. Aftercompletion of reaction (monitored by TLC, 20% ethyl acetate-hexaneR_(f)=0.5), a saturated solution of K₂CO₃ was added to the reactionmixture and the organic layer was separated and washed with saturatedK₂CO₃ solution. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel (100-200 mesh),eluting with 5% ethyl acetate in hexanes to afford 1-benzyl 4-ethyl5-oxoazepane-1,4-dicarboxylate as a colorless oil. Yield=13.0 g, 48%LCMS m/z=320.25 (M+1); purity=>90% by ¹H NMR.

Reaction step 2. Synthesis of 1-benzyl4-ethyl-5-hydroxyazepane-1,4-dicarboxylate

Sodium borohydride (1.5 g, 40.8 mmol, 1.0 eq) was added portion wise toa solution of 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (13.0 g,40.8 mmol, 1.0 eq) in EtOH (130 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h. After completion of the reaction (monitored byTLC, 30% ethyl acetate-hexane R_(f)=0.3), the reaction mixture wasquenched by addition of a saturated aqueous solution of potassium sodiumtartrate and the solid was filtered. The filtrate was diluted withdichloromethane and washed with a saturated solution of aqueouspotassium sodium tartrate followed by water. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure togive 10.0 g of crude 1-benzyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylatethat was used in the next step without purification or characterization.

Reaction step 3. Synthesis of 1-benzyl 4-ethyl2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

To a solution of 1-benzyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylate(10.0 g, 31.0 mmol, 1.0 eq) in THF (100 mL) and triethylamine (12.6 mL93.0 mmol, 3.0 eq) at 0° C., methanesulfonyl chloride (5.9 mL, 78 mmol,2.5 eq) was added in three portions over 6 h. After completion of thereaction (monitored by TLC, 20% ethyl acetate-hexane R_(f)=0.3), thereaction mixture was diluted with dichloromethane and washed withsaturated aqueous NaHCO₃. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue (20g) was dissolved in THF (10 vol), DBU (11.4 mL, 46.5 mmol, 1.5 eq) wasadded and the reaction mixture and heated 80° C. for 1 h. Aftercompletion of reaction (monitored by TLC, 20% ethyl acetate-hexaneR_(f)=0.6), the reaction mixture was diluted with dichloromethane andwashed with saturated aqueous NaHCO₃. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography on silica gel(100-200 mesh), eluting with 10% ethyl acetate in hexanes to afford1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (6.5 g,80%) as a colorless oil. LCMS m/z=304.16 (M+1); purity=91%.

Reaction step 4. Synthesis of benzyl4-(hydroxymethyl)azepane-1-carboxylate

LiBH₄ (0.80 g, 36.3 mmol, 2.0 eq) was added to a solution of 1-benzyl4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (5.50 g, 18.2mmol, 1 eq) in THF (55 mL) at 0° C. in three portions over 30 min. Thereaction mixture was heated to 60° C. for 6 h. After completion of thereaction (monitored by TLC, 20% ethyl acetate-hexane (R_(f)=0.2), thereaction mixture was cooled to 0° C., quenched with ice cold water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica gel(100-200 mesh), eluting with a 0-20% gradient of ethyl acetate inhexanes to obtain benzyl 4-(hydroxymethyl)azepane-1-carboxylate (2.80 g,60%) as a colourless oil. LCMS m/z=264.25 (M+1), purity=95%.

Reaction step 5. Synthesis of benzyl4-(tosyloxymethyl)azepane-1-carboxylate

To a solution of benzyl 4-(hydroxymethyl)azepane-1-carboxylate (2.80 g,10.6 mmol, 1 eq) in dichloromethane (28 mL) and triethylamine (4.3 mL,31.9 mmol, 3.0) eq at 0° C., tosyl chloride (3.0 g, 15.7 mmol, 1.5 eq)was added and the reaction mixture was stirred overnight at roomtemperature. After completion of the reaction (monitored by TLC, 20%ethyl acetate-hexane (R_(f)=0.4), the reaction mixture was poured intoice cold water and extracted with dichloromethane. The organic extractwas dried over anhydrous sodium sulfate and the solvents were removedunder reduced pressure. The crude product was purified by flash columnchromatography on silica gel (100-200 mesh), eluting with a 0-10%gradient of ethyl acetate in hexanes to obtain benzyl4-(tosyloxymethyl)azepane-1-carboxylate as a colourless oil (2.30 g,63%). LCMS m/z=418.19 (M+1); purity=96.2%.

Intermediate 5 Synthesis of benzyl2-(tosyloxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

Reaction step 1. Synthesis of ethyl 3-bromopropiolate

Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution ofethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at roomtemperature. The resulting reaction mixture was stirred for 5 min, thenNBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixturestirred for 2 h at room temperature. After completion of the reaction(monitored by TLC, 5% ethyl acetate-hexane, R_(f)=0.55), the reactionmixture was filtered through a celite pad, washing with acetone. Thefiltrate was concentrated under reduced temperature (25-30° C.) toafford an oil. The crude product was purified by flash columnchromatography on silica gel (100-200 mesh), eluting with 10% diethylether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58%) as ayellow oil. LCMS m/z=176.91 (M+1).

Reaction step 2. Synthesis of 7-tert-butyl 2-ethyl3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate

A mixture of methyl 3-bromopropiolate (5.00 g, 28.2 mmol, 1.0 eq) andtert-butyl 1H-pyrrole-1-carboxylate (14.00 g, 84.7 mmol, 3.0 eq) in asealed tube was heated to 90° C. for 14 h. After completion of thereaction (monitored by TLC, 5% ethyl acetate-hexane, R_(f)=0.3), Thereaction mixture was purified without work up by flash columnchromatography on silica gel (100-200 mesh), eluting with 5% ethylacetate in hexanes to afford 7-tert-butyl 2-methyl3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g,20%) as a brown oil. LCMS m/z=344.2 (M+1); purity=75%.

Reaction step 3. Synthesis of 7-tert-butyl 2-methyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

To a stirred solution of 7-tert-butyl 2-methyl3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (15.0 g,43.7 mmol, 1.0 eq) in ethanol (300 mL), was added palladium on carbon(2.0 g) and the reaction mixture was stirred at room temperature for 3 hunder a hydrogen atmosphere maintained by a hydrogen filled balloon.After completion of the reaction (monitored by TLC, 10% ethylacetate-hexane R_(f)=0.5), the mixture was filtered through a celitepad, washing with methanol. The filtrate was evaporated under reducedpressure to obtain 7-tert-butyl 2-ethyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (9.90 g, 85%) as a lightbrown oil. LCMS m/z=255.25 (M-14) purity by ¹H NMR>90%.

Reaction step 4. Synthesis of ethyl7-azabicyclo[2.2.1]heptane-2-carboxylate

A solution of 4M HCl in dioxane (100 mL, 400 mmol, 3.0 eq) was slowlyadded to a stirred solution of 7-tert-butyl 2-ethyl3-bromo-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (20.0 g, 74.3 mmol,1.0 eq) in dioxane (400 mL) at 0° C. and the reaction mixture wasstirred at room temperature for 2 h. After completion of the reaction(monitored by TLC, 30% ethyl acetate-hexane, R_(f)=0.01), solvent wasremoved under reduced pressure and the residue was dried under vacuum toafford ethyl 7-azabicyclo[2.2.1]heptane-2-carboxylate HCl (12.0 g, 96%)as a yellow sticky mass. LCMS m/z=156.12 (M+1); crude purity by ¹HNMR˜90%.

Reaction step 5. Synthesis of 7-benzyl 2-ethyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

To a stirred solution of ethyl 7-azabicyclo[2.2.1]heptane-2-carboxylate(12.0 g, 71.0 mmol, 1.0 eq) in dichloromethane (120 mL) was addedtriethylamine (25.9 mL, 355 mmol, 5.0 eq) at 0° C., and then benzylchloroformate (13.3 g, 78.1 mmol, 1.1 eq) was slowly added. The mixturewas stirred for 14 h at room temperature. After completion of thereaction (monitored by TLC, 30% ethyl acetate-hexane R_(f)=0.7), thereaction was quenched with saturated sodium bicarbonate solution, theproduct extracted with dichloromethane and the solvent was concentrated.The crude product was purified by flash column chromatography on silicagel (100-200 mesh), eluting with 10% ethyl acetate in hexane to obtain7-benzyl 2-ethyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (11.8 g,58%) as a yellow oil. LCMS m/z=290.18 (M+1).

Reaction step 6. Synthesis of benzyl2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

Lithium borohydride (5.50 g, 264 mmol, 4.0 eq) was slowly added to astirred solution of 7-benzyl 2-ethyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (20.0 g, 66.0 mmol, 1.0 eq)in tetrahydrofuran (400 mL) at 0° C. and the mixture was stirred at 60°C. for 12 h. After completion of the reaction (monitored by TLC, 30%ethyl acetate-hexanes, R_(f)=0.15), the mixture was quenched with icecold water and the product was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and concentrated to affordbenzyl 2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (13.6g, 80%) as a light yellow oil. LCMS m/z=262.12 (M+1).

Reaction step 7. Synthesis of benzyl2-(tosyloxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To a stirred solution of benzyl2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (16.0 g, 61.3mmol, 1.0 eq) in dichloromethane (160 mL) was added triethylamine (42.7mL, 306 mmol, 5.0 eq) at 0° C., followed by the slow addition of tosylchloride (17.4 g, 91.9 mmol, 1.5 eq). The reaction mixture was stirredfor 14 h at room temperature. After completion of the reaction(monitored by TLC, 30% ethyl acetate-hexane R_(f)=0.7), the reactionmixture was diluted with dichloromethane and washed with saturatedsodium bicarbonate solution. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The crude masswas purified by flash column chromatography on silica gel (100-200mesh), eluting with 15% ethyl acetate in hexanes to obtain benzyl2-(tosyloxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (16.0 g,64%) as an off white solid. LCMS m/z=416.14 (M+1).

Intermediate 6 Synthesis of benzyl4-((5-bromo-1H-indazol-1-yl)methyl)piperidine-1-carboxylate and benzyl4-((5-bromo-2H-indazol-2-yl)methyl)piperidine-1-carboxylate

Sodium hydride (60% suspension in mineral oil, 3.65 g, 91 mmol, 1.5 eq)was added to a solution of 5-bromo-1H-indazole (12.0 g, 60.9 mmol, 1 eq)in DMF (100 mL) at 0° C. After 15 minutes, a solution of benzyl4-(tosyloxymethyl)piperidine-1-carboxylate (29.5 g, 73.0 mmol, 1.2 eq)in DMF (200 mL) was added to the above mixture and stirring wascontinued over night at room temperature. After completion of thereaction (monitor by LCMS & TLC, 25% ethyl acetate-hexane, R_(f)=0.5),the mixture was poured into ice cold water and extracted with ethylacetate. The organic extract was washed with water followed by brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel, 100-200 mesh, eluting with a 0-10%gradient of ethyl acetate in hexanes to obtain benzyl4-((5-bromo-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (15.9 g,60%) as a yellow sticky mass. LCMS purity: 89.76%; (ES⁺): m/z 428.3(M+H⁺); tr=2.50 min. The second product to elute was benzyl4-((5-bromo-2H-indazol-2-yl)methyl)piperidine-1-carboxylate (5.90 g,22%) was isolated as yellow sticky mass. LCMS: purity: 94.3%; (ES⁺): m/z428.3 (M+H⁺); tr=2.40 min.

Intermediate 7 Synthesis of1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Reaction step 1. Synthesis of benzyl4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.42 g, 12.3 mmol, 1.5 eq) was added to a solution of benzyl4-((5-bromo-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (3.5 g, 8.2mmol, 1.0 eq) in a mixture of DMF and water (9:1, 45 mL) at roomtemperature. Potassium carbonate (3.39 g, 24.5 mmol, 3 eq) was thenadded and the reaction mixture was purged with argon for 20 min.PdCl₂(dppf)dichloromethane (0.668 g, 0.818 mmol, 0.1 eq) was added,argon was passed through the solution for a further 10 min and themixture was heated at 80° C. for 16 h. After completion of the reaction(monitored by TLC, 50% ethyl acetate-hexanes, R_(f)=0.20), the reactionmixture was cooled to room temperature and filtered through a bed ofdiatomaceous earth washing with ethyl acetate. The combined filtrate waswashed with water followed by brine, the organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel 100-200 mesh, eluting with a 40-50% gradient of ethyl acetatein hexanes to afford benzyl4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate(1.85 g, 45%) as colourless oil. LCMS purity: 77.54%; (ES): m/z 500.5(M+H⁺); tr=2.32 min.

Reaction step 2. Synthesis of1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

To a solution of benzyl4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate(1.85 g, 160 mmol, 1.0 eq) in EtOH (25 mL), 10% Pd on charcoal (50%moisture, 0.50 g) was added under an argon atmosphere and the mixturewas stirred under a H₂ atmosphere at 40 psi in a Parr apparatus for 16h. After completion of reaction (monitored by TLC, 10%MeOH-dichloromethane; R_(f)=0.1), catalyst was removed by filtrationthrough a bed of diatomaceous earth, washing with ethyl acetate. Thecombined filtrate was concentrated under reduced pressure and the crudeproduct was purified by column chromatography on neutral alumina,eluting with a 0-10% gradient of MeOH in dichloromethane to afford1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.825 g, 61%) as off white solid. LCMS purity: 87.50%; (ES⁺): m/z366.29 (M+H⁺); tr=1.28 min.

Intermediate 81-(pyrrolidin-3-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Using the methods described for the synthesis of Intermediates 6 and 7above and starting with 5-bromo-1H-indazole and benzyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate,1-(pyrrolidin-3-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazolecan be prepared.

Intermediate 91-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Using the method described for the synthesis of Intermediate 6 andreaction step 1 of Intermediate 7 above, starting with5-bromo-1H-indazole and (1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate,1-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazolecan be prepared. Debenzylation to give1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazolecan be accomplished by treatment of a methanol solution of the abovecompound with ammonium formate and Pd(OH)₂/C at reflux for severalhours.

Intermediate 101-(azepan-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Using the method described for the synthesis of Intermediates 6 and 7above and starting with 5-bromo-1H-indazole and benzyl4-((tosyloxy)methyl)azepane-1-carboxylate,1-(azepan-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazolecan be prepared.

Intermediate 111-(7-azabicyclo[2.2.1]heptan-2-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Using the method described for the synthesis of Intermediates 6 and 7above and starting with 5-bromo-1H-indazole and benzyl2-((tosyloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate,1-(azepan-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazolecan be prepared.

Intermediates 12 and 13

Step 1. Synthesis of 1-benzyl-5-methylpyrrolidin-2-one

To a stirred solution of 5-methylpyrrolidin-2-one (200 g, 2.02 mol, 1.0eq) in DMF (1.5 L), sodium hydride (60% suspension on mineral oil, 131g, 3.3 mol, 1.5 eq) was slowly added at 0° C., followed by benzylbromide (292 mL, 2.42 mol, 1.2 eq) and the mixture was allowed stir atroom temperature for 3 h. After completion of the reaction (monitored byTLC, 20% ethyl acetate-hexane, KMnO₄, R_(f)=0.45), the reaction wasquenched by adding ice cubes and the mixture was extracted with ethylacetate (500 mL). The organic extract was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (100-200mesh), eluting with 10% ethyl acetate in hexanes to afford1-benzyl-5-methylpyrrolidin-2-one in two fractions. The first fractioncontained 200 g of 1-benzyl-5-methylpyrrolidin-2-one (yield 52.4%,LC-MS: purity: 95%) and the second fraction contained an additional 100g (yield 26.2%, LC-MS: purity: 83%) as an oily liquid. (ES⁺): m/z 190.1(M+H⁺); tr=1.21, 1.61 min.

Step 2: Synthesis of methyl1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylate and1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid

n-BuLi (2.5M in hexanes, 215 mL, 0.528 mol, 2.0 eq) was slowly added toa stirred solution of diisopropyl amine (78.4 mL, 0.555 mol, 2.1 eq) inTHF (500 mL), at −78° C. and stirring was continued for 40 min, duringwhich time, the temperature of the reaction was allowed to rise to −20°C. The mixture was again cooled to −78° C., a solution of1-benzyl-5-methylpyrrolidin-2-one (50 g, 0.265 mol, 1.0 eq) in THF (5.0L) was added and stirring was continued for 45 min, maintaining the sametemperature. Then dimethyl carbonate (44.5 mL, 0.528 mol, 2.0 eq) wasadded to the above mixture and stirring continued for 5 h, during whichtime, the temperature of the reaction mixture was allowed to rise toroom temperature. After completion of the reaction (monitored by TLC,30% ethyl acetate-hexanes, KMnO₄, R_(f)=0.65), the reaction was quenchedby slowly adding 1M aq NH₄Cl at 0° C. and the mixture was extracted withethyl acetate (3 L). The organic extract was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to affordcrude methyl 1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylate (4.5 g,6.8% mixture of diastereomers) as a brown sticky mass. LC-MS purity:37.5%, (ES⁺) m/z: 248.1 (M+H⁺), tr=1.32, 1.71.

The aqueous extract was acidified with 2N HCl to pH 2 and againextracted with ethyl acetate (5 L). The organic extract was dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to afford 1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid(40.1 g, 65.2%, mixture of diastereomers) brown sticky mass. LC-MSpurity: 68.9% (ES⁺): m/z 234.1 (M+H⁺). tr=1.46, 1.49.

Step 3: Synthesis of (1-benzyl-5-methylpyrrolidin-3-yl) methanol

Lithium aluminium hydride (2M in THF, 253 mL, 252 mmol, 2.35 eq) wasadded to a stirred solution of1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid (25 g, 107 mmol,1.0 eq) in THF (250 mL), at 0° C. and stirring was continued for 3 h,during time which temperature of the reaction was allowed to rise toroom temperature. After completion (monitored by TLC, 30% ethylacetate-hexanes, KMnO₄, R_(f)=0.65), the reaction was again cooled to 0°C. and excess lithium aluminium hydride was quenched by addition of 15mL of water very slowly over a period of 3 h. The white precipitateformed was filtered through a celite bed and the filtrate wasconcentrated under reduced pressure to afford(1-benzyl-5-methylpyrrolidin-3-yl) methanol (9 g, mixture ofdiastereomers) as a brown sticky mass, which was used as such in thenext step. LC-MS purity: 68.03%. (ES⁺): m/z 206.1 (M+H⁺). tr=0.50, 0.60.

Step 4: Synthesis of (1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate

To a stirred solution of (1-benzyl-5-methylpyrrolidin-3-yl)methanol (40g, 195 mmol, 1.0 eq) in dichloromethane (250 mL), triethylamine (81.5mL, 59 mmol, 3.0 eq) was slowly added at 0° C. followed by tosylchloride (44.6 g, 234 mmol, 1.2 eq) and the mixture was allowed to stirat room temperature for 12 h. After completion of the reaction(monitored by TLC, 50% ethyl acetate-hexanes, R_(f)=0.65), saturatedaqueous NaHCO₃ solution (25 mL) was added and the organic layer wasseparated. The aqueous layer was further extracted with dichloromethane(120 mL). The combined organic extract was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford(1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate (32 g,mixture of diastereomers) as brown sticky mass. LC-MS purity: 94.65%.(ES⁺): m/z 360.16 (M+H⁺). tr=1.40, 1.53.

Step 5: Separation of cis and trans isomers of(1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate

A mixture of the cis and trans isomers of(1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate (63 g)was purified by column chromatography on silica gel, (5 kg) 100-200mesh, eluting with 10% ethyl acetate in hexanes to obtaincis-(1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate(19.6 g, 31.1%) as a pale brown liquid andtrans-(1-benzyl-5-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate(25.9 g, 41.1) as an off white solid.

Data for cis-(1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate (Intermediate 12):

LC-MS purity: 91.78%; (ES⁺): m/z 360.32 (M+H⁺); tr=4.42 min.

¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.31-7.22 (m, 7H),3.95 (d, J=8.4 Hz, 1H), 3.87 (dd, J=1.6, 8.4 Hz, 2H), 3.06 (d, J=13.2Hz, 1H), 2.62 (dd, J=2.4, 10.4 Hz, 1H), 2.44 (s, 3H), 2.42-2.00 (m, 4H),1.09-1.00 (m, 4H).

Data for trans-(1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate (Intermediate 13):

LC-MS purity: 94.64%; (ES⁺): m/z 360.32 (M+H⁺); tr=4.64 min.

¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.0 Hz, 2H), 7.33-7.21 (m, 7H),3.98 (m, 3H), 3.04 (d, J=12.8 Hz, 1H), 2.95 (dd, J=2.0, 7.2 Hz, 1H),2.45 (s, 3H), 2.42-2.37 (m, 2H), 1.79 (d, J=8.4 Hz, 1H), 1.66-1.54 (m,2H), 1.12 (d, 3H).

Intermediate 14 Synthesis ofrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Step 1. Synthesis ofrac.-cis-1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Sodium hydride (60% suspension in mineral oil, 309 mg, 10.2 mmol, 2.5eq) was added to DMF (10.0 mL) followed by addition of5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole (1.1 g, 4.1mmol) and the mixture was stirred at room temperature for 30 min.Rac.-cis-(1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate (1.4 g, 4.1 mmol) was added to the abovemixture and stirring continued at room temperature for 16 h. Aftercompletion of the reaction (monitored by TLC, 100% ethyl acetate-hexanesR_(f)=0.4), ice cubes were added followed by water and the mixture wasextracted with ethyl acetate. The organic extract was dried overanhydrous sodium sulfate, filtered and solvents evaporated from thefiltrate under reduced pressure. The residue was purified by columnchromatography on silica gel, 100-200 mesh, eluted with 30% gradient ofethyl acetate in hexanes to affordrac.-cis-1-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.5 g, 26.8%) as a pale yellow sticky solid. LCMS purity: 88.4%; (ES⁺):m/z 456.53 (M+H⁺); tr=2.40 min.

In addition,rac.-cis-2-((l-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2H-indazole(0.220 g, 11.8%; m/z 456.3 M+H⁺, tr=1.63 min) was obtained as a sideproduct, which was discarded.

Step 2. Synthesis ofrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

To a solution ofrac.-cis-1-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.250 g, 0.54 mmol) in methanol (5 mL), was added Pd(OH)₂ on carbon(20% w/w, 50% moisture, 0.050 g) followed by ammonium formate (0.138 g,2.1 mmol) at room temperature and the mixture was refluxed for 3 h.After completion of the reaction (monitored by TLC, 100% ethyl acetateR_(f)=0.1), the mixture was cooled to room temperature, the catalyst wasfiltered and the filtrate was concentrated under reduced pressure toaffordrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.200 g, quantitative) as a pale yellow gummy solid. LC-MS purity:91.7%, (ES⁺): m/z 366.36 (M+H⁺). tr=1.32 min.

Intermediate 15 Synthesis ofrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Step 1. Synthesis ofrac.-trans-1-((l-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Sodium hydride (60% suspension in mineral oil, 490 mg, 13 mmol) wasadded to DMF (15.0 mL) followed by addition of5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole (1.40 g,5.2 mmol, 1.0 eq) and the mixture was stirred at room temperature for 30min. rac.-trans-(1-benzyl-5-methylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate (1.8 g, 5.2 mmol) was added to the abovemixture and stirring was continued at room temperature for 16 h. Aftercompletion of the reaction (monitored by TLC, 100% ethyl acetate-hexanesR_(f)=0.4), ice cubes were added followed by water and the mixture wasextracted with ethyl acetate. The organic extract was dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel, 100-200 mesh, eluting with 30% ethyl acetate in hexanes toaffordrac.-trans-1-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.6 g, 25%) as a pale yellow sticky solid. LCMS purity: 80.4%; (ES⁺):m/z 456.43 (M+H⁺); tr=3.49 min. In addition, trans2-((1-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2H-indazole(m/z 456.6 M+H⁺; tr=1.58 min) was formed, but not isolated.

Step 2. Synthesis ofrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

To a solution ofrac.-trans-1-((l-benzyl-5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.600 g, 1.31 mmol) in methanol (10 mL) was added Pd(OH)₂ on carbon(20% w/w, 50% moisture, 0.100 g) followed by ammonium formate (0.332 g,5.27 mmol) at room temperature and the mixture was refluxed for 3 h.After completion of the reaction (monitored by TLC, 100% ethyl acetateR_(f)=0.1), the mixture was cooled to room temperature, the mixture wasfiltered a celite bed and the filtrate was concentrated under reducedpressure to affordrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.400 g, crude) as an off white sticky solid, which was used in thenext step without further purification. LC-MS purity: 72.6%, (ES⁺): m/z366.5 (M+H⁺). tr=1.33 min.

Intermediate 16 Synthesis of(1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate

Reaction step 1: Synthesis of 1-benzyl-5,5-dimethylpyrrolidin-2-one

To a solution of 5,5-dimethylpyrrolidin-2-one (35.0 g, 310 mmol, 1.0 eq)in DMF (350 mL), NaH (60% suspension in paraffin oil, 18.6 g, 465 mmol,1.5 eq) was slowly added followed by benzyl bromide (44.0 mL, 372 mmol,1.2 eq) at 0° C., the mixture was allowed to warm to room temperaturewith continuous stirring and stirred at rt for 16 h. After completion ofthe reaction (monitored by TLC, 50% ethyl acetate-hexane, R_(f)=0.50),reaction mixture was quenched by the addition of ice cubes and extractedwith ethyl acetate (500 mL). The organic extract was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel (100-200 mesh), eluting with a 40% gradient of ethyl acetatein hexanes to afford 1-benzyl-5,5-dimethylpyrrolidin-2-one (40.0 g,63.6%) as colourless viscous liquid. LCMS purity: 90.58%; (ES⁺): m/z204.2 (M+H⁺); tr=1.77 min.

Reaction step 2. Synthesis of methyl1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate

A stirred solution of diisopropyl amine (63.0 mL, 394 mmol, 2.0 eq) inTHF (400 mL) was cooled to −78° C. n-BuLi (2.5M in hexanes, 164.0 mL,394 mmol, 2.0 eq) was slowly added. The mixture was allowed to warm to−20° C. and was stirred at −20° C. for 90 min. The mixture was thenagain cooled to −78° C. and a solution of1-benzyl-5,5-dimethylpyrrolidin-2-one (40.0 g, 197 mmol, 1.0 eq) in THF(100 mL) was added slowly to the above mixture. Stirring was continuedat −78° C. for 60 min followed by addition of dimethyl carbonate (36.0mL, 413 mmol, 2.1 eq) slowly, while maintaining the temperature at −78°C. After completion of the addition, the mixture was allowed to warm toroom temperature over 4 h. After completion of the reaction (monitoredby TLC, 50% ethyl acetate-hexanes, R_(f)=0.55), the reaction mixture wasquenched by the slow addition of 1M HCl at 0° C. and the mixture wasextracted with ethyl acetate. The organic extract was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford methyl1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (20.0 g, 40%) ascolorless viscous liquid. LCMS purity: 90.0%; (ES⁺): m/z 262.01 (M+H⁺);tr=1.82 min.

Reaction step 3. Synthesis of(1-benzyl-5,5-dimethylpyrrolidin-3-yl)methanol

Lithium aluminium hydride (2M in hexane, 145 mL, 306 mmol, 4.0 eq) wasadded slowly to a stirred solution of methyl1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (20.0 g, 76.6 mmol,1.0 eq) in THF (200 mL) at 0° C. and stirring was continued while themixture was allowed to warm up to room temperature over a period of 6 h.After completion of the reaction (monitored by TLC, 30% ethylacetate-hexanes, R_(f)=0.25), the reaction was quenched by the slowaddition of 20 mL of water and 20 mL of 15% aqueous NaOH followed by 40mL of water at 0° C. The precipitated solid was removed by filtering themixture through a bed of celite and the filtrate was concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel (100-200 mesh), eluting with 40% ethylacetate in hexanes to afford(1-benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (9.0 g, 53.8%) ascolorless gel. LCMS purity: 89.15%; (ES⁺): m/z 220.30 (M+H⁺); tr=3.11min.

Reaction step 4. Synthesis of(1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate

To a solution of (1-benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (5.0 g23 mmol, 1.0 eq) in dichloromethane (50 mL), triethylamine (9.3 mL, 68mmol, 3.0 eq) was added, p-toluene sulfonyl chloride (5.2 g, 27.4 mmol,1.2 eq) at 0° C. and the reaction mixture was stirred at roomtemperature for 12 h. After completion of the reaction (monitored byTLC, 50% ethyl acetate-hexane, R_(f)=0.65), the reaction mixture waspoured into ice-cold water and extracted with dichloromethane. Theorganic extract was washed with brine, dried over anhydrous sodiumsulfate, filtered and cencentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (100-200mesh), eluting with a 10-15% gradient of ethyl acetate in hexanes toafford (1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl4-methylbenzenesulfonate (5.8 g, 68%) as colorless gel. LCMS purity:78.3%; (ES⁺): m/z 374.32 (M+H⁺); tr=4.28 min.

Intermediate 171-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Step 1

Sodium hydride (60% suspension in mineral oil, 0.224 g, 5.59 mmol) wasadded to DMF (10.0 mL) followed by addition of5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole (1.0 g,3.73 mmol) and the mixture was stirred at room temperature for 30 min.(1-Benzyl-5,5-dimethylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate(1.53 g, 4.47 mmol) was added to the above mixture and stirring wascontinued at room temperature for 6 h. After completion of the reaction(monitored by TLC, 60% ethyl acetate-hexanes R_(f)=0.4), ice cubes wereadded followed by water and the mixture was extracted with ethylacetate. The organic extract was washed with water followed by brine,dried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel, 100-200 mesh, eluting with a 45-50%gradient of ethyl acetate in hexanes to afford1-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(1.54 g, 88%) as a brown sticky mass. LC-MS purity: 86.42%; (ES⁺): m/z470.71 (M+H⁺), tr=1.55 min.

Note: In that reaction,2-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2H-indazole(m/z 470.6 M+H′, tr=1.62 min) was also formed as a minor side product,but not isolated.

Step 2. Synthesis of1-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

To a solution of1-((1-benzyl-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(1.54 g, 3.28 mmol) in methanol (20 mL), was added Pd(OH)₂ on carbon(20% w/w, 50% moisture, 0.150 g) followed by ammonium formate (0.827 g,15.7 mmol) at room temperature and the mixture was refluxed for 3 h.After completion of the reaction (monitored by TLC, 10% MeOH indichloromethane R_(f)=0.2), the mixture was cooled to room temperature,the catalyst was filtered off by filtering through a celite bed and thefiltrate was concentrated under reduced pressure to afford1-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.880 g, 71%) as a pale yellow solid. LC-MS purity: 95.8%, (ES⁺): m/z380.50 (M+H⁺). tr=1.38 min.

Example 1 Synthesis of3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1-one

3-Phenylpropanoyl chloride (0.115 g, 0.68 mmol, 1.2 eq) andtriethylamine (0.127 mL, 0.90 mmol, 1.66 eq) were added to a stirredsolution of1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.200 g 0.547 mmol, 1.0 eq) in dichloromethane (10 mL) at 0° C. and themixture was stirred at room temperature for 2 h. After completion of thereaction (monitored by TLC, 100% ethyl acetate, R_(f)=0.5), chilledwater was added and the mixture was extracted with dichloromethane. Theorganic extract was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel 100-200 mesh, elution with 100% ofethyl acetate to obtain3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1-one(0.210 g, 75%) as a white solid. LCMS purity: 97.24%; (ES⁺): m/z 498.39(M+H⁺); tr=3.88 min.

Example 2 Synthesis of2-cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone

Using the experimental procedure described in example 1 using2-cyclohexylacetyl chloride (0.110 g, 0.68 mmol, 1.2 eq), triethylamine(0.126 mL, 0.89 mmol, 1.66 eq) and1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.20 g, 0.54 mmol, 1.0 eq) in dichloromethane (10 mL),2-cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone(0.150 g, 56%) was obtained as a white solid. LCMS purity: 98.33%;(ES⁺): m/z 490.60 (M+H⁺); tr=2.30 min.

Example 3 Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one

To a solution of3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1-one(0.20 g, 0.40 mmol, 1.0 eq) in MeOH (10 mL) was added p-toluenesulfonicacid (0.471 g, 2.73 mmol, 5.0 eq) at room temperature and the mixturewas stirred at for 6 h. After completion of reaction (monitored by TLC,100% Ethyl acetate R_(f)=0.40), methanol was removed under reducedpressure, chilled water was added and pH adjusted to 7 with saturatedaqueous NaHCO₃. The mixture was extracted with ethyl acetate, the ethylacetate layer was washed with water followed by brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was triturated with diethyl ether to afford1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one(0.098 g, 59%) as an off white solid. LC-MS: purity 99.57%; (ES⁺) m/z:414.19 (M+H⁺); tr=1.78 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H),8.16 (bs, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.69-7.63 (m, 2H), 7.28-7.14(m, 5H), 4.36 (d, J=13.2 Hz, 1H), 4.28 (d, J=7.2 Hz, 2H), 3.82 (d,J=13.2 Hz, 1H), 2.87 (t, J=12.0 Hz, 1H), 2.78 (t, J=8.0 Hz, 2H),2.60-2.54 (m, 2H), 2.52-2.43 (m, 1H), 2.18-2.09 (m, 1H), 1.48-1.39 (m,2H), 1.12-1.00 (m, 2H).

Example 4 Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-cyclohexylethanone

Using the experimental procedure in example 3, starting with2-cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone(0.15 g, 0.31 mmol, 1.0 eq) and p-toluenesulfonic acid (0.264 g, 1.53mmol, 5.0 eq) in methanol (10 mL),1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-cyclohexylethanone(0.096 g, 60%) was obtained as off white solid. LC-MS: purity 99.83%;(ES⁺) m/z: 406.20 (M+H⁺); tr=1.95 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.87(s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.65 (q, J=11.2 Hz &8.8 Hz, 2H), 4.36 (d, J=13.6 Hz, 1H), 4.31 (d, J=6.8 Hz, 2H), 3.84 (d,J=13.2 Hz, 1H), 2.90 (t, J=12.8 Hz, 1H), 2.45 (t, J=12.0 Hz, 1H),2.21-2.12 (m, 1H), 2.13 (d, J=6.4 Hz, 2H), 1.68-1.56 (m, 6H), 1.47 (d,J=11.2 Hz, 2H), 1.23-1.05 (m, 5H), 0.93-0.84 (m, 2H).

Example 5 Synthesis of2-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone

HATU (0.31 g, 0.824 mmol, 1.5 eq) was added to a mixture of phenylacetic acid (0.089 g, 0.65 mmol, 1.2 eq) and DIPEA (0.21 g, 1.65 mmol, 3eq) in DMF (4 mL) at 0° C. The resulting mixture stirred for 15 min,1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.20 g, 0.55 mmol, 1.0 eq) was added and the mixture was stirred for 12h at room temperature. After completion of the reaction (monitored byTLC, 100% ethyl acetate R_(f)=0.40), the mixture was poured into icecold water, extracted with ethyl acetate and the ethyl acetate extractwas washed with water, followed by brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel 100-200 mesh, eluting with 100% of ethyl acetate to afford2-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone(0.210 g, 79%) as a pale yellow solid. LCMS purity: 99.48%; (ES⁺): m/z484.5 (M+H⁺); tr=1.64 min.

Example 6 Synthesis of4-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)butan-1-one

The experimental procedure described in example 5, starting with4-phenylbutanoic acid (0.107 g, 0.65 mmol, 1.2 eq), HATU (0.312 g, 0.820mmol, 1.5 eq) and1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.20 g, 0.547 mmol, 1.0 eq) in DMF (5 mL),4-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)butan-1-one(0.185 g, 68%) was obtained as a white solid. LCMS purity: 96.87% (ES⁺):m/z 512.6 (M+H⁺); tr=2.26 min.

Example 7 Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-phenylethanone

To a solution of2-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone(0.200 g, 0.413 mmol, 1 eq) in MeOH (10 mL) was added p-toluenesulfonicacid (0.471 g, 2.73 mmol, 5 eq) at room temperature and the mixture wasstirred for 6 h. After completion of the reaction (monitored by TLC,100% ethyl acetate, R_(f)=0.4), methanol was removed under reducedpressure, chilled water was added and the pH adjusted to 7 withsaturated aqueous NaHCO₃. The mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with water followed by brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was triturated with diethyl ether to afford1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-phenylethanone(0.120 g, 78%) as an off white solid. LCMS: purity 99.39%; (ES⁺) m/z:400.38 (M+H⁺); tr=3.25 min. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.88 (s, 1H),8.18 (bs, 1H), 8.01 (s, 1H), 7.93 (bs, 1H), 7.92 (s, 1H), 7.76-7.62 (m,2H), 7.30-7.18 (m, 5H), 4.35 (d, J=13.2 Hz, 1H), 4.27 (d, J=6.8 Hz, 2H),3.92 (d, J=14.0 Hz, 1H), 3.67 (d, J=2.8 Hz, 2H), 2.90 (t, J=11.6 Hz,1H), 2.51-2.49 (m, 1H), 2.15-2.11 (m, 1H), 1.48 (d, J=12.0 Hz, 1H), 1.38(d, J=12.0 Hz, 1H), 1.13-0.97 (m, 2H).

Example 8 Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-4-phenylbutan-1-one

Using the experimental procedure described in example 7 starting with4-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)butan-1-one(0.170 g, 0.33 mmol, 1.0 eq) and p-toluenesulfonic acid (0.286 g, 1.66mmol, 5.0 eq) in methanol (10 mL),1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-4-phenylbutan-1-one(0.074 g, 52%) was obtained as a white solid. LC-MS: purity: 98.82%;(ES⁺): m/z 428.38 (M+H⁺); tr=3.53 min. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.85(s, 1H), 8.06 (bs, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.70-7.63 (m, 2H),7.29-7.25 (m, 2H), 7.18-7.14 (m, 3H), 4.35 (d, J=12.4 Hz, 1H), 4.30 (d,J=7.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 2.89 (t, J=12.4 Hz, 1H), 2.56(t, J=7.2 Hz, 2H), 2.46 (t, J=11.2 Hz, 1H), 2.27 (t, J=7.6 Hz, 2H),2.21-2.11 (m, 1H), 1.79-1.71 (m, 2H), 1.50-1.41 (m, 2H), 1.16-1.06 (m,2H).

Examples 9 and 10

Using the methods described in examples 1 and 3, and starting with1-(pyrrolidin-3-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product  9

(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)(phenyl)methanone 10

1-(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one

Examples 11-16

Using the methods described in examples 1 and 3, and starting with1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 11

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(phenyl)methanone 12

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2-phenylethanone 13

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one 14

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(cyclopentyl)methanone 15

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(cyclohexyl)methanone 16

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2,2-dimethylpropan-1-one

Example 17 Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-3-phenylpropan-1-one

Step 1. Synthesis of1-(2,2-dimethyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one

Triethylamine (0.45 ml, 3.29 mmol) was slowly added to a solution of1-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.250 g, 0.659 mmol,) in dichloromethane (10 mL), at 0° C. followed by3-phenylpropanoyl chloride (0.132 g, 0.791 mmol) and the mixture wasallowed to stir at room temperature for 4 h. After completion of thereaction (monitored by TLC, 70% ethyl acetate-hexanes, R_(f)=0.4),saturated aqueous sodium bicarbonate was added and the mixture wasextracted with dichloromethane. The organic extract was dried overanhydrous sodium sulphate, filtered and solvents concentrated underreduced pressure to obtain a crude product, which was purified by columnchromatography on silica gel, 100-200 mesh, eluting using a gradient of55-60% ethyl acetate-hexanes to afford1-(2,2-dimethyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.210 g, 62.3%) as an off white solid. LC-MS purity: 97.64%. (ES⁺): m/z512.60 (M+H⁺), tr=2.25 min.

Step 2. Synthesis of1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-3-phenylpropan-1-one

To a solution of1-(2,2-dimethyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.207 g, 0.405 mmol) in methanol (10 mL), p-toluenesulfonic acid (0.384g, 2.02 mmol) was added and the mixture was stirred at room temperaturefor 6 h. After completion of the reaction (monitored by TLC, 5% methanolin dichloromethane, R_(f)=0.35), saturated aqueous sodium bicarbonatewas added and the mixture was extracted with ethyl acetate. The crudeproduct was triturated with diethyl ether to obtain1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-3-phenylpropan-1-one(0.135 g, 78%) as a white solid. LC-MS purity: 97.9%; (ES⁺): m/z 428.50(M+H⁺); tr=1.94 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (bs, 1H), 8.18(s, 1H), 8.02 (s, 1H), 7.93 (s, 2H), 7.62-7.73 (m, 2H), 7.09-7.23 (m,5H), 4.37-4.49 (m, 2H) 3.45-3.53 (m, 1H), 3.19-3.30 (m, 1H), 2.64-2.80(m, 3H), 2.30-2.48 (m, 2H), 1.68-1.75 (m, 1H), 1.55-1.65 (m, 1H), 1.58(s, 3H), 1.25 (s, 3H).

Examples 18-20

Using the methods described in example 17, and starting with1-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 18

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(phenyl)methanone 19

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-2-phenylethanone 20

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(cyclopentyl)methanone

Examples 21-24

Using the methods described in examples 1 and 3, and starting with1-(azepan-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 21

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(phenyl)methanone22

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-2-phenylethanone23

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-3-phenylpropan-1-one 24

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(cyclopentyl)methanone

Examples 25-28

Using the methods described in examples 1 and 3, and starting with1-(7-azabicyclo[2.2.1]heptan-2-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 25

(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(phenyl)methanone 26

1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylethanone 27

1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-3-phenylpropan-1-one 28

1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2,2-dimethylpropan-1-one

Example 29 Synthesis of1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Benzenesulfonyl chloride (0.16 mL, 1.23 mmol, 1.5 eq) and triethylamine(0.57 mL, 4.1 mmol, 5.0 eq) were added to a stirred solution of1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.3 g 0.81 mmol, 1.0 eq) in dichloromethane (10 mL) at 0° C. and themixture was stirred at room temperature for 4 h. After completion of thereaction (monitored by TLC, 5% MeOH in dichloromethane; R_(f)=0.45),chilled water was added and the mixture was extracted withdichloromethane. The organic extract was dried over anhydrous sodiumsulphate, filtered and solvents were evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel,100-200 mesh, eluting with a 65-75% gradient of ethyl acetate in hexanesto afford1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.3 g, 72%) as pale yellow solid. LCMS purity: 85.32%; (ES⁺): m/z506.50 (M+H⁺); tr=2.21 min.

Example 30 Synthesis of1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

To a solution of1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.3, 0.59 mmol, 1.0 eq) in MeOH (8 mL) was added p-toluenesulfonic acidmono hydrate (0.564 g, 2.97 mmol, 5.0 eq) at room temperature and themixture was stirred at room temperature for 12 h. After completion ofthe reaction (monitored by TLC, 5% methanol in dichloromethaneR_(f)=0.35), methanol was removed under reduced pressure, chilled waterwas added and the pH adjusted to 7 with saturated aqueous NaHCO₃. Themixture was then extracted with ethyl acetate, the ethyl acetate layerwas washed with water followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was triturated with diethyl ether to obtain1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole(0.060 g, 24%) as an off white solid. LC-MS: Purity: 96.93%; (ES⁺): m/z422.14 (M+H⁺); tr=2.44 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (bs, 1H),8.16 (s, 1H), 7.98 (s, 2H), 7.92-7.59 (m, 8H), 4.27 (d, J=7.2 Hz, 2H),3.63 (d, J=11.6 Hz, 2H), 2.17 (t, J=11.2 Hz, 2H), 1.95-1.85 (m, 1H),1.52 (d, J=11.2 Hz, 2H), 1.34-1.23 (m, 2H).

Example 31 Synthesis of1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Phenylmethanesulfonyl chloride (0.117 g, 0.49 mmol, 1.5 eq) andtriethylamine (0.30 mL, 2.05 mmol, 5.0 eq) were added to a stirredsolution of1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.150 g 0.41 mmol, 1.0 eq) in dichloromethane (5 mL) at 0° C. and themixture was stirred at room temperature for 4 h. After completion of thereaction (monitored by TLC, 5% MeOH in dichloromethane; R_(f)=0.45),chilled water was added and the mixture was extracted withdichloromethane. The organic extract was dried over anhydrous sodiumsulfate, filtered and solvents evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel100-200 mesh, eluting with a 60-70% gradient of ethyl acetate in hexanesto obtain1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.040 g, 19%) as an off white solid. LCMS purity: 90.68%; (ES⁺): m/z520.60 (M+H⁺); tr=2.22 min.

Example 32 Synthesis of1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

To a solution of1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.04, 0.077 mmol, 1.0 eq) in MeOH (5 mL) was added p-toluenesulfonicacid mono hydrate (0.073 g, 0.38 mmol, 5.0 eq) at room temperature andthe mixture was stirred at room temperature for 12 h. After completionof the reaction (monitored by TLC, 5% methanol in dichloromethaneR_(f)=0.35), methanol was removed under reduced pressure, chilled waterwas added and the pH adjusted to 7 with saturated aqueous NaHCO₃. Themixture was then extracted with ethyl acetate. The ethyl acetate layerwas washed with water followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was triturated with diethyl ether to obtain1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole(0.025 g, 74%) as a pale yellow solid. LC-MS: Purity: 95.78%; (ES⁺): m/z436.14 (M+H⁺); tr=1.89 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (bs, 1H),8.18 (s, 1H), 8.02 (bs, 1H), 7.92 (s, 2H), 7.70-7.31 (m, 7H), 4.33 (s,2H), 4.30 (d, J=6.8 Hz, 2H), 3.52 (d, J=12.4 Hz, 2H), 2.63 (t, J=11.2Hz, 2H), 2.00-1.98 (m, 1H), 1.47 (d, J=11.2 Hz, 2H), 1.25-1.17 (m, 2H).

Example 33 Preparation ofrac.-cis-1-((-5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Step 1. Synthesis ofrac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Triethylamine (0.414 g, 4.1 mmol) was slowly added to a solution ofrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.300 g, 0.82 mmol) in dichloromethane (5 mL), at 0° C. followed bybenzenesulfonyl chloride (0.173 g, 0.98 mmol) and the mixture wasallowed to stir at room temperature for 2 h. After completion of thereaction (monitored by TLC, 5% Methanol-dichloromethane, R_(f)=0.55),saturated aqueous sodium bicarbonate was added and the mixture wasextracted with dichloromethane. The organic extract was dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onneutral alumina, using 60% ethyl acetate-hexanes as eluent to affordrac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.220 g, 53%) as an off white sticky solid. LC-MS purity: 90.4%. (ES⁺):m/z 506.19 (M+H⁺), tr=2.28 min.

Step 2. Synthesis ofrac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

To a solutionrac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.220 g, 0.44 mmol) in methanol (5 mL), p-toluenesulfonic acid (0.116g, 0.60 mmol) was added and the mixture was stirred at room temperaturefor 6 h. After completion of the reaction (monitored by TLC, 10%methanol in dichloromethane, R_(f)=0.5), saturated aqueous sodiumbicarbonate was added and the mixture was extracted with ethyl acetate.The organic extract was dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedby preparative HPLC to obtainrac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole(0.145 g, 79%) as a white solid. LC-MS purity: 95.2%; (ES⁺): m/z 422. 4(M+H⁺); tr=1.85 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (bs, 1H), 8.18(bs, 1H), 8.0 (s, 1H), 7.94 (bs, 1H), 7.92 (s, 1H), 7.73 (d, J=7.6 Hz,2H), 7.62-7.71 (m, 2H), 7.53-7.62 (m, 3H), 4.35 (d, J=6.4 Hz, 2H),3.42-3.53 (m, 1H), 3.35-3.42 (m, 1H), 3.13-3.25 (m, 1H), 1.87-2.05 (m,2H), 1.26-1.42 (m, 4H).

Example 34 Preparation ofrac.-trans-1-((-5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Step 1. Synthesis ofrac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Triethylamine (0.273 g, 2.70 mmol) was slowly added to a solution ofrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.200 g, 0.54 mmol) in dichloromethane (5 mL), at 0° C. followed bybenzenesulfonyl chloride (0.115 g, 0.65 mmol, 1.2 eq) and the mixturewas allowed to stir at room temperature for 2 h. After completion of thereaction (monitored by TLC, 100% Ethyl acetate, R_(f)=0.55), saturatedaqueous sodium bicarbonate was added and the mixture was extracted withdichloromethane. The organic extract was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on neutral alumina, using60% ethyl acetate-hexanes as eluent to affordrac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.130 g, 47%) as an off white sticky solid. LC-MS purity: 92.9%. (ES⁺):m/z 506.19 (M+H⁺), tr=2.21 min.

Step 2. Synthesis ofrac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

To a solutionrac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.130 g, 0.25 mmol) in methanol (5 mL), p-toluenesulfonic acid (0.073g, 0.38 mmol) was added and the mixture was stirred at room temperaturefor 6 h. After completion of the reaction (monitored by TLC, 10%methanol in dichloromethane, R_(f)=0.5), saturated aqueous sodiumbicarbonate was added and the mixture was extracted with ethyl acetate.The organic extract was dried over anhydrous sodium sulphate, filteredand concentrated under reduced pressure. The crude product was purifiedby preparative HPLC to obtainrac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole(0.05 g, 46%) as an off white solid. LC-MS purity: 95.74%; (ES⁺): m/z422.4 (M+H⁺); tr=1.89 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (bs, 1H),8.06 (bs, 2H), 7.97 (s, 1H), 7.91 (s, 1H), 7.76 (d, J=7.6 Hz, 2H),7.56-7.73 (m, 4H), 4.09-4.28 (m, 2H), 3.69-3.80 (m, 1H), 3.38-3.48 (m,1H), 2.93 (t, J=9.2 Hz, 1H), 2.77-2.89 (m, 1H), 1.45-1.55 (m, 1H),1.3-1.43 (m, 1H), 1.18 (d, J=6.4 Hz, 3H).

Example 35 Preparation of1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Step 1. Synthesis of1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole

Triethylamine (0.45 ml, 3.29 mmol) was slowly added to a solution of1-((5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.250 g, 0.659 mmol, 1.0 eq) in dichloromethane (10 mL), at 0° C.followed by benzenesulfonyl chloride (0.174 g, 0.791 mmol) and themixture was allowed to stir at room temperature for 4 h. Aftercompletion of the reaction (monitored by TLC, 70% ethyl acetate-hexanes,R_(f)=0.35), saturated aqueous sodium bicarbonate was added and themixture was extracted with dichloromethane. The organic extract wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel, 100-200 mesh, using 60-65% ethylacetate-hexanes as eluent to afford1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.225 g, 65.7%) as an off white solid. LC-MS purity: 96.54%. (ES⁺): m/z520.5 (M+H⁺), tr=2.28 min.

Step 2. Synthesis of1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

To a solution of1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.220 g, 0.423 mmol) in methanol (10 mL), p-toluenesulfonic acid (0.402g, 2.119 mmol) was added and the mixture was stirred at room temperaturefor 6 h. After completion of the reaction (monitored by TLC, 5% methanolin dichloromethane, R_(f)=0.35), saturated aqueous sodium bicarbonatewas added and the mixture was extracted with ethyl acetate. The crudeobtained after evaporation of solvents from the organic phase wastriturated with diethyl ether to obtain1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole(0.170 g, 92%) as a white solid. LC-MS purity: 96.36%; (ES⁺): m/z 436.4(M+H⁺); tr=2.00 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (bs, 1H), 8.18(s, 1H), 8.02 (s, 1H), 7.93 (d, J=4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H),7.56-7.75 (m, 5H), 4.42 (d, J=7.2 Hz, 2H) 3.46-3.53 (m, 1H), 3.15 (t,J=9.2 Hz, 1H), 2.70-2.85 (m, 1H), 1.75-1.83 (m, 1H), 1.62-1.73 (m, 1H),1.36 (s, 3H), 1.27 (s, 3H).

Example 36 Synthesis of1-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the 4-chlorobenzene sulfonyl chloride,1-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazolewas prepared. LC-MS purity: 97.8%; (ES⁺): m/z 456.25 (M+H⁺); tr=4.01min. ¹H NMR (400 MHz, DMSO-d₆) δ12.87 (bs, 1H), 8.17 (s, 1H), 7.99 (s,1H), 7.92-7.90 (m, 2H), 7.71-7.61 (m, 6H), 4.28 (d, J=6.8 Hz, 2H), 3.61(d, J=11.6 Hz, 2H), 2.22 (t, J=11.2 Hz, 2H), 1.90-1.85 (m, 1H), 1.52 (d,J=11.2 Hz, 2H), 1.35-1.23 (m, 2H).

Example 37 Synthesis of1-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand 4-fluorobenzene sulfonyl chloride,1-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazolewas prepared. LC-MS purity: 98.1%; (ES⁺): m/z 440.30 (M+H⁺); tr=3.85min. ¹H NMR (400 MHz, DMSO-d₆) 12.87 (bs, 1H), 8.17 (s, 1H), 7.99 (s,1H), 7.92-7.90 (m, 2H), 7.78-7.74 (m, 2H), 7.66-7.61 (m, 2H), 7.44 (t,J=8.8 Hz, 2H), 4.28 (d, J=6.8 Hz, 2H), 3.61 (d, J=12.0 Hz, 2H), 2.20 (t,J=11.2 Hz, 2H), 1.98-1.85 (m, 1H), 1.52 (d, J=11.2 Hz, 2H), 1.34-1.23(m, 2H).

Example 38 Synthesis of4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-ylsulfonyl)benzonitrile

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand 4-cyanobenzene sulfonyl chloride,4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-ylsulfonyl)benzonitrilewas prepared. LC-MS purity: 97.9%; (ES⁺): m/z 447.32 (M+H⁺); tr=3.75min. ¹H NMR (400 MHz, DMSO-d₆) 12.87 (bs, 1H), 8.17 (s, 1H), 8.08 (d,J=8.4 Hz, 2H), 7.98 (s, 1H), 7.93-7.85 (m, 4H), 7.64 (s, 2H), 4.28 (d,J=6.8 Hz, 2H), 3.65 (d, J=11.6 Hz, 2H), 2.29 (t, J=11.2 Hz, 2H),1.94-1.87 (m, 1H), 1.52 (d, J=11.2 Hz, 2H), 1.33-1.23 (m, 2H).

Example 39 Synthesis of5-(1H-pyrazol-4-yl)-1-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-1H-indazole

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand pyridine-3-sulfonyl chloride,5-(1H-pyrazol-4-yl)-1-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-1H-indazolewas prepared. LC-MS purity: 99.0%; (ES⁺): m/z 423.27 (M+H⁺); tr=3.44min. ¹H NMR (400 MHz, DMSO-d₆) 12.87 (bs, 1H), 8.86 (s, 2H), 8.12-8.09(m, 3H), 7.99 (s, 1H), 7.91 (s, 1H), 7.67-7.61 (m, 3H), 4.28 (d, J=6.8Hz, 2H), 3.66 (d, J=11.6 Hz, 2H), 2.29 (t, J=11.2 Hz, 2H), 1.97-1.90 (m,1H), 1.53 (d, J=11.2 Hz, 2H), 1.33-1.23 (m, 2H).

Example 40 Synthesis of1-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand 3-fluorobenzene sulfonyl chloride,1-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazolewas prepared. LC-MS purity: 98.5%; (ES⁺): m/z 440.30 (M+H⁺); tr=3.93min. ¹H NMR (400 MHz, DMSO-d₆) 12.87 (bs, 1H), 8.17 (s, 1H), 7.98 (s,1H), 7.93-7.91 (m, 2H), 7.69-7.50 (m, 6H), 4.28 (d, J=6.8 Hz, 2H), 3.64(d, J=11.6 Hz, 2H), 2.50 (t, J=11.2 Hz, 2H), 1.96-1.87 (m, 1H), 1.52 (d,J=11.2 Hz, 2H), 1.35-1.23 (m, 2H).

Example 41 Synthesis of1-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Using the method described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand 2-fluorobenzene sulfonyl chloride,1-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazolewas prepared. LC-MS purity: 99.4%; (ES⁺): m/z 440.30 (M+H⁺); tr=3.66min. ¹H NMR (400 MHz, DMSO-d₆) 12.87 (bs, 1H), 8.17 (s, 1H), 7.99 (s,1H), 7.93-7.91 (m, 2H), 7.76-7.61 (m, 4H), 7.47-7.37 (m, 2H), 4.29 (d,J=6.8 Hz, 2H), 3.66 (d, J=11.6 Hz, 2H), 2.29 (t, J=11.2 Hz, 2H),2.07-1.97 (m, 1H), 1.54 (d, J=11.2 Hz, 2H), 1.33-1.23 (m, 2H).

Examples 42-44

Using the methods described in examples 29 and 30, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the benzene sulfonyl chlorides shown in the table below, thefollowing can be prepared:

Example Acyl Chloride Product 42

5-(1H-pyrazol-4-yl)-1-((1-tosylpiperidin-4-yl)methyl)-1H-indazole 43

3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)sulfonyl)benzonitrile 44

1-((1-((4-(difluoromethyl)phenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Example 45

Using the methods described in examples 1 and 3, and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chloride shown in the table below, the following can beprepared:

Example Acyl Chloride Product 45

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)phenylmethanone

Example 46 Synthesis ofrac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one

Step 1. Synthesis ofrac.-cis-1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one

Triethylamine (0.272 g, 2.7 mmol) was slowly added to a solution ofrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.200 g, 0.54 mmol) in dichloromethane (8 mL), at 0° C. followed byhydrocinnamoyl chloride (0.111 g, 0.65 mmol) and the mixture was allowedto stir at room temperature for 12 h. After completion of the reaction(monitored by TLC, 100% ethyl acetate, R_(f)=0.5), saturated aqueoussodium bicarbonate (10 mL) was added and the mixture was extracted withdichloromethane (15 mL). The organic extract was dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on neutral alumina, using60% ethyl acetate-hexanes as eluent to affordrac.-cis-1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.250 g, 91.9%) as an off white sticky solid. LC-MS purity: 94.5%.(ES⁺): m/z 498.41 (M+H⁺), tr=2.17 min.

Step 2. Synthesis ofrac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one

To a solution ofrac.-cis-1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.100 g, 0.20 mmol, 1.0 eq) in methanol (5 mL), p-toluenesulfonic acid(0.057 g, 0.30 mmol, 1.5 eq) was added and the mixture was stirred atroom temperature for 6 h. After completion of the reaction (monitored byTLC, 10% methanol in dichloromethane, R_(f)=0.15), saturated aqueoussodium bicarbonate was added and the mixture was extracted with ethylacetate. The organic extract was concentrated and the residue waspurified by preparative HPLC to obtainrac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one(0.050 g, 60%) as an off white solid. LC-MS purity: 97.29%; (ES⁺): m/z414.31 (M+H⁺); tr=3.67 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (bs, 1H),8.17 (bs, 1H), 8.03 (s, 1H), 7.93 (s, 2H), 7.6-7.76 (m, 2H), 7.05-7.25(m, 5H), 4.36-4.51 (m, 2H) 3.7-3.95 (m, 1H), 3.48-3.60 (m, 1H),3.12-3.23 (m, 1H), 2.7-2.85 (m, 2H), 2.33-2.48 (m, 2H), 2.05-2.15 (m,1H), 1.27-1.50 (m, 1H), 1.10-1.27 (m, 4H).

Example 47 Synthesis ofrac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one

Step 1. Synthesis ofrac.-trans-1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one

Triethylamine (0.273 g, 2.7 mmol) was slowly added to a solution ofrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole(0.200 g, 0.54 mmol) in dichloromethane (8 mL), at 0° C. followed byhydrocinnamoyl chloride (0.109 g, 0.65 mmol) and the mixture was allowedto stir at room temperature for 12 h. After completion of the reaction(monitored by TLC, 100% ethyl acetate, R_(f)=0.5), saturated aqueoussodium bicarbonate was added and the mixture was extracted withdichloromethane (15 mL). The organic extract was dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure toobtain a crude product, which was purified by olumn chromatography onneutral alumina, using 60% ethyl acetate-hexanes as eluent to affordrac.-trans1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.150 g, 55%) as an off white sticky solid. LC-MS purity: 88.5%. (ES⁺):m/z 498.34 (M+H⁺), tr=2.16 min.

Step 2. Synthesis ofrac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one

To a solution ofrac.-trans-1-(2-methyl-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one(0.150 g, 0.300 mmol,) in methanol (5 mL), p-toluenesulfonic acid (0.087g, 0.45 mmol) was added and the mixture was stirred at room temperaturefor 6 h. After completion of the reaction (monitored by TLC, 10%methanol in dichloromethane, R_(f)=0.15), saturated aqueous sodiumbicarbonate was added and the mixture was extracted with ethyl acetate.The organic extract was concentrated and the residue was purified bypreparative HPLC to obtainrac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one(0.050 g, 40%) as a white solid. LC-MS purity: 98.96%; (ES⁺): m/z 414.24(M+H⁺); tr=1.81 min. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (bs, 1H), 8.18(bs, 1H), 8.0-8.07 (m, 1H), 7.93 (s, 2H), 7.6-7.78 (m, 2H), 7.10-7.30(m, 5H), 4.32-4.50 (m, 2H) 3.95-4.15 (m, 1H), 3.40-3.48 (m, 1H),3.13-3.25 (m, 1H), 2.72-2.95 (m, 3H), 2.31-2.48 (m, 2H), 1.72-1.85 (m,1H), 1.48-1.63 (m, 1H), 0.98-1.13 (m, 3H).

Examples 48-55

Using the methods described in examples 5 and 7 and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the carboxylic acids shown in the table below, the following can beprepared:

Example Carboxylic Acid Product 48

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2-fluorophenyl)propan-1-one 49

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(4-fluorophenyl)propan-1-one 50

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(3-fluorophenyl)propan-1-one 51

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one 52

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,4-difluorophenyl)propan-1-one 53

1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(p-tolyl)propan-1-one 54

4-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile 55

3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile

Examples 56-64

Using the methods described in examples 1 and 3 and starting with1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the carboxylic acid chlorides shown in the table below, thefollowing can be prepared:

Example Carboxylic Acid Product 56

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(phenyl)methanone 57

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2-fluorophenyl)methanone 58

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(4-fluorophenyl)methanone 59

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,3-difluorophenyl)methanone 60

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,4-difluorophenyl)methanone 61

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(p-tolyl)methanone 62

4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile 63

3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile 64

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(3-fluorophenyl)methanone

Examples 65-72

Using the methods described in example 17, and starting with1-(5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 65

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(4-fluorophenyl)methanone 66

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-fluorophenyl)methanone 67

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2-fluorophenyl)methanone 68

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2,3-difluorophenyl)methanone 69

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(p-tolyl)methanone 70

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-methoxyphenyl)methanone 71

3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidine-1-carbonyl)benzonitrile 72

(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(m-tolyl)methanone

Examples 73-78

Using the methods described in example 5 and 7 and starting withrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the carboxylic acids shown in the table below, the following can beprepared:

Example Carboxylic Acid Product 73

rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one 74

rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one 75

rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one 76

rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one 77

rac.-trans-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrile 78

rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one

Examples 79-84

Using the methods described in example 5 and 7 and starting withrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the carboxylic acids shown in the table below, the following can beprepared:

Example Carboxylic Acid Product 79

rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one 80

rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one 81

rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one 82

rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one 83

rac.-cis-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrile 84

rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one

Examples 85-92

Using the methods described in example 46, and starting withrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 85

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(4-fluorophenyl)methanone 86

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(3-fluorophenyl)methanone 87

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(2-fluorophenyl)methanone 88

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(2,3-difluorophenyl)methanone 89

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(p-tolyl)methanone 90

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(3-methoxyphenyl)methanone 91

rac.-cis-3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidine-1-carbonyl)benzonitrile 92

rac.-cis-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(m-tolyl)methanone

Examples 93-102

Using the methods described in example 47, and starting withrac.-trans-1-(5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 93

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(4-fluorophenyl)methanone 94

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(3-fluorophenyl)methanone 95

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylprolidin-1-yl)(2-fluorophenyl)methanone 86

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(2,3-difluorophenyl)methanone 97

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(p-tolyl)methanone 98

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(3-methoxyphenyl)methanone 99

rac.-trans-3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidine-1-carbonyl)benzonitrile 100 

rac.-trans-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(m-tolyl)methanone

Examples 101-108

Using the methods described in example 34, and starting withrac.-trans-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the benzene sulfonyl chlorides shown in the table below, thefollowing can be prepared:

Example Sulfonyl Chloride Product 101

rac.-trans-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 102

rac.-trans-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 103

rac.-trans-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 104

rac.-trans-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 105

rac.-trans-1-((5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 106

rac.-trans-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 107

rac.-trans-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile 108

rac.-trans-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Examples 109-116

Using the methods described in example 33, and starting withrac.-cis-1-((5-methylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the benzene sulfonyl chlorides shown in the table below, thefollowing can be prepared:

Example Sulfonyl Chloride Product 109

rac.-cis-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 110

rac.-cis-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 111

rac.-cis-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 112

rac.-cis-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 113

rac.-cis-1-(((3R,5S)-5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 114

rac.-cis-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 115

rac.-cis-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile 116

rac.-cis-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Examples 117-124

Using the methods described in example 35, and starting with1-(5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazoleand the acid chlorides shown in the table below, the following can beprepared:

Example Acyl Chloride Product 117

1-((1-((4-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 118

1-((1-((3-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 119

1-((1-((2-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 120

1-((1-((2,3-difluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 121

1-((5,5-dimethyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 122

3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrile 123

1-((5,5-dimethyl-1-(m-tolylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole 124

4-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrile 125

1-((1-((4-fluoro-3-methylphenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole

Example 126 Human T_(H)17 Cytokine Inhibition as Measured by ELISA

Peripheral blood mononuclear cells (PBMCs) were sourced from freshlyprepared leukocyte enriched plasma (buffy coat) from healthy donors (NewYork Blood Center). PBMCs were isolated by density gradientcentrifugation using Ficoll-Paque™ PLUS (GE Healthcare). Human CD4+ Tcells were seeded into 96-well plates (5×10⁴ cells/well) and activatedwith plate-bound anti-human (h)-CD3 antibody and soluble h-aCD28 (bothat 1 ug/ml; eBioscience) and differentiated into T_(H)17 cells with 20ng/mL h-IL-6, 5 ng/mL h-TGF-β1, 10 ng/mL h-IL-23 (eBioscience) and 10ng/mL IL-1β (Miltenyi Biotec) in serum-free TexMACS Medium (MiltenyiBiotec) supplemented with 1% Penicillin/Streptomycin (Lonza) for 3 days.CD4+ T cells propagated under T_(H)17-polarizing conditions werecultured in the presence or absence of various concentrations ofcompounds with a final concentration of 0.1% DMSO. Supernatants werecollected and stored at −20° C. until assayed for IL-17A, IL-17F andIL-21 levels by “Ready-Set-Go” ELISA kits (eBioscience) as permanufacturer's instructions. Endpoint absorbance was read at 450 nmusing a microplate reader (Perkin Elmer). The half maximal inhibitoryconcentrations (IC₅₀) for representative compounds of the invention weredetermined by GraphPad Prism® software and presented in the table below(wherein “nd” is “not determined”):

Example IL-17A IL-17F IL-22 IL-21 Number [IC50 uM] [IC50 uM] [IC50 uM][IC50 uM] 3 <10 <10 nd <10 4 <10 <10 nd <10 7 <10 <10 nd <10 8 <10 <10nd <10 19 <10 <10 nd nd 30 <10 <10 <10 <10 32 <10 <10 <10 <10 33 <10 <10nd <10 34 <10 <10 nd <10 35 <10 <10 nd <10 37 <10 <10 nd nd 38 <10 <10nd nd 39 <10 <10 nd nd 42 <10 <10 nd nd 43 <10 <10 nd nd 44 <10 <10 ndnd 46 <10 <10 nd <10 47 <10 <10 nd <10

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

We claim:
 1. A compound of formula (I):

wherein: A is a monocyclic or bicyclic 5- to 8-membered heterocyclicring having one ring carbon replaced by N as shown, said ring optionallymono- or bi-substituted on one or more ring carbons independently with aC₁-C₆ alkyl group; X is —(CH₂)_(n)—, —O—, or —NH—; Y is —(CH₂)_(p)—,—O—, or —S—, with the proviso that X and Y are not both a heteroatom; Zis —(CH₂)_(q)—; R₁ is —C₁-C₆ alkyl, optionally substituted with one ormore —OH, halogen or —CN, phenyl, optionally mono- or bisubstitutedindependently with halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy,alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl, cycloalkyl,optionally substituted, heterocycle, optionally substituted or a 5- or6-membered heteroaryl group having one or more ring carbonsindependently replaced by N, O or S, said heteroaryl optionally mono- orbisubstituted independently with halogen, alkoxy, C₁-C₆ alkyl, —CN,nitrile or perfluorinated C₁-C₆ alkyl; R₂ is a 5- to 7-memberedheteroaryl group having one, two or three ring carbons independentlyreplaced by N, O or S, said heteroaryl optionally mono- orbi-substituted independently with C₁-C₆ alkyl, —CN or (═O); n is 0 or 1;p is 0 or 1; and q is 0, 1 or 2, or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1, wherein A isunsubstituted piperidinyl, pyrrolidinyl, [2,2,1]bicycloazepinyl orazepanyl.
 3. The compound according to claim 1, wherein A ispiperidinyl, pyrrolidinyl or azepanyl mono- or bi-substitutedindependently with a C₁-C₆ alkyl group.
 4. The compound according toclaim 1, wherein A is piperidinyl, pyrrolidinyl or azepanylmono-substituted with methyl.
 5. The compound according to claim 1,wherein A is piperidinyl, pyrrolidinyl or azepanyl bi-substituted withmethyl.
 6. The compound according to claim 1, wherein X is —CH₂—, —O—,or —NH—.
 7. The compound according to claim 1, wherein Y is —O—.
 8. Thecompound according to claim 1, wherein R₁ is —C₁-C₆ alkyl.
 9. Thecompound according to claim 1, wherein R₁ is methyl, ethyl, propyl ort-butyl.
 10. The compound according to claim 1, wherein R₁ isunsubstituted phenyl.
 11. The compound according to claim 1, wherein R₁is phenyl substituted with halogen, alkylsulfonyl, alkoxy, —CN, alkyl,or C₁-C₆ alkyl.
 12. The compound according to claim 1, wherein R₁ iscycloalkyl.
 13. The compound according to claim 1, wherein R₁ is anunsubstituted 5- or 6-membered heteroaryl group having one or more ringcarbons replaced by N.
 14. The compound according to claim 1, wherein R₂is an unsubstituted 5- to 7-membered heteroaryl group having one, two orthree ring carbons replaced by N.
 15. The compound according to claim 1,wherein R₂ is unsubstituted pyrazolyl or triazolyl.
 16. The compoundaccording to claim 1, wherein R₂ is unsubstituted pyrazolyl.
 17. Thecompound according to claim 1, wherein R₂ is linked via a carbon atom.18. The compound according to claim 1, having the formula (Ia):

wherein: X is —(CH₂)_(n)—, —O—, or —NH—; Y is —(CH₂)_(p)—, —O—, or —S—,with the proviso that X and Y are not both a heteroatom; Z is—(CH₂)_(q)—; R₁ is —C₁-C₆ alkyl, optionally substituted with one or more—OH, halogen or —CN, phenyl, optionally mono- or bisubstitutedindependently with halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy,alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl, cycloalkyl,optionally substituted, heterocycle, optionally substituted or a 5- or6-membered heteroaryl group having one or more ring carbonsindependently replaced by N, O or S, said heteroaryl optionally mono- orbisubstituted independently with halogen, alkoxy, C₁-C₆ alkyl, —CN,nitrile or perfluorinated C₁-C₆ alkyl; R₂ is a 5- to 7-memberedheteroaryl group having one, two or three ring carbons independentlyreplaced by N, O or S, said heteroaryl optionally mono- orbi-substituted independently with C₁-C₆ alkyl, —CN or (═O); R₃, R₄, R₅and R₆ are, independently of each other, H or —C₁-C₆ alkyl; n is 0 or 1;p is 0 or 1; and q is 0 1 or 2, or a pharmaceutically acceptable saltthereof.
 19. The compound according to claim 1, having the formula (Ib):

wherein: X is —(CH₂)_(n)—, —O—, or —NH; Y is —(CH₂)_(p)—, —O—, or —S—,with the proviso that X and Y are not both a heteroatom; Z is—(CH₂)_(q)—; R₁ is —C₁-C₆ alkyl, optionally substituted with one or more—OH, halogen or —CN, phenyl, optionally mono- or bisubstitutedindependently with halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy,alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl, cycloalkyl,optionally substituted, heterocycle, optionally substituted or a 5- or6-membered heteroaryl group having one or more ring carbonsindependently replaced by N, O or S, said heteroaryl optionally mono- orbisubstituted independently with halogen, alkoxy, C₁-C₆ alkyl, —CN,nitrile or perfluorinated C₁-C₆ alkyl; R₂ is a 5- to 7-memberedheteroaryl group having one, two or three ring carbons independentlyreplaced by N, O or S, said heteroaryl optionally mono- orbi-substituted independently with C₁-C₆ alkyl, —CN or (═O); R₃ and R₄are, independently of each other, H or —C₁-C₆ alkyl; n is 0 or 1; p is 0or 1; and q is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.20. The compound according to claim 1, having the formula (Ic):

wherein: X is —(CH₂)_(n)—, —O—, or —NH; Y is —(CH₂)_(p)—, —O—, or —S—,with the proviso that X and Y are not both a heteroatom; Z is—(CH₂)_(q)—; R₁ is —C₁-C₆ alkyl, optionally substituted with one or more—OH, halogen or —CN, phenyl, optionally mono- or bisubstitutedindependently with halogen, alkoxy, C₁-C₆ alkyl, —CN, -alkylsulfonyloxy,alkylsulfonyl, halo-C₁-C₆ alkyl or C₁-C₅ cycloalkyl, cycloalkyl,optionally substituted, heterocycle, optionally substituted or a 5- or6-membered heteroaryl group having one or more ring carbonsindependently replaced by N, O or S, said heteroaryl optionally mono- orbisubstituted independently with halogen, alkoxy, C₁-C₆ alkyl, —CN,nitrile or perfluorinated C₁-C₆ alkyl; R₂ is a 5- to 7-memberedheteroaryl group having one, two or three ring carbons independentlyreplaced by N, O or S, said heteroaryl optionally mono- orbi-substituted independently with C₁-C₆ alkyl, —CN or (═O); R₃, R₄, R₅and R₆ are, independently of each other, H or —C₁-C₆ alkyl; n is 0 or 1;p is 0 or 1; and q is 0, 1 or 2, or a pharmaceutically acceptable saltthereof.
 21. The compound according to claim 1, wherein said compoundis:1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-cyclohexylethanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-2-phenylethanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-4-phenylbutan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-3-phenylpropan-1-one,rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-oneorrac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one.22. The compound according to claim 1, wherein said compound is:1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)phenylmethanone,(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)(phenyl)methanone,1-(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)-3-phenylpropan-1-one,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(phenyl)methanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2-phenylethanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-phenylpropan-1-one,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)(cyclopentyl)methanone,(3-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)(cyclohexyl)methanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-2,2-dimethylpropan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)-2-phenylethanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(phenyl)methanone,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-3-phenylpropan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)-2-phenylethanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)azepan-1-yl)(cyclopentyl)methanone,(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(phenyl)methanone,1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylethanone,1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-3-phenylpropan-1-oneor1-(2-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2,2-dimethylpropan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2-fluorophenyl)propan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(4-fluorophenyl)propan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(3-fluorophenyl)propan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(2,4-difluorophenyl)propan-1-one,1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-(p-tolyl)propan-1-one,4-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile,3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-oxopropyl)benzonitrile,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2-fluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(4-fluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,3-difluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(2,4-difluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(p-tolyl)methanone,4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile,3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidine-1-carbonyl)benzonitrile,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)(3-fluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(4-fluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-fluorophenyl)methanone.(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2-fluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(2,3-difluorophenyl)methanone,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(p-tolyl)methanone,4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(3-methoxyphenyl)methanone,3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidine-1-carbonyl)benzonitrile,(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)(m-tolyl)methanone,rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one,rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one,rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one,rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,rac.-trans-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrile,rac.-trans-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one,rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(4-fluorophenyl)propan-1-one,rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(3-fluorophenyl)propan-1-one,rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2-fluorophenyl)propan-1-one,rac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(2,3-difluorophenyl)propan-1-one,rac.-cis-3-(3-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-oxopropyl)benzonitrileorrac.-cis-1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)-3-(m-tolyl)propan-1-one.23. A compound of formula (II):

wherein: A is a monocyclic or bicyclic 5- to 8-membered heterocyclicring having one ring carbon replaced by N as shown, said ring optionallymono- or bi-substituted on one or more ring carbons independently with aC₁-C₆ alkyl group; Z is —(CH₂)_(q)—; Y is —(CH₂)_(p)— or O; R₁ is —C₁-C₆alkyl, optionally substituted with one or more —OH, halogen or —CN,phenyl, optionally mono- or bisubstituted independently with halogen,alkoxy, C₁-C₆ alkyl, —CN, alkylsulfonyloxy, alkylsulfonyl, halo-C₁-C₆alkyl or C₁-C₅ cycloalkyl, cycloalkyl, optionally substituted,heterocycle, optionally substituted or a 5- or 6-membered heteroarylgroup having one or more ring carbons independently replaced by N, O orS, said heteroaryl optionally mono- or bisubstituted independently withhalogen, alkoxy, C₁-C₆ alkyl, —CN, nitrile or perfluorinated C₁-C₆alkyl; R₂ is a 5- to 7-membered heteroaryl group having one, two orthree ring carbons independently replaced by N, O or S, said heteroaryloptionally mono- or bi-substituted independently with C₁-C₆ alkyl, —CNor (═O); and q is 0, 1 or 2, p is 0 or 1, or a pharmaceuticallyacceptable salt thereof.
 24. The compound according to claim 23, whereinA is unsubstituted piperidinyl, pyrrolidinyl, [2,2,1]bicycloazepinyl orazepanyl.
 25. The compound according to claim 23, wherein A ispiperidinyl, pyrrolidinyl or azepanyl mono- or bi-substitutedindependently with a C₁-C₆ alkyl group.
 26. The compound according toclaim 23, wherein A is piperidinyl, pyrrolidinyl or azepanylmono-substituted with methyl.
 27. The compound according to claim 23,wherein A is piperidinyl, pyrrolidinyl or azepanyl bi-substituted withmethyl.
 28. The compound according to claim 23, wherein R₁ is —C₁-C₆alkyl.
 29. The compound according to claim 23, wherein R₁ is methyl,ethyl, propyl or t-butyl.
 30. The compound according to claim 23,wherein R₁ is unsubstituted phenyl.
 31. The compound according to claim23, wherein R₁ is phenyl substituted with halogen, alkylsulfonyl,alkoxy, —CN, alkyl, or C₁-C₆ alkyl.
 32. The compound according to claim23, wherein R₁ is cycloalkyl.
 33. The compound according to claim 23,wherein R₁ is an unsubstituted 5- or 6-membered heteroaryl group havingone or more ring carbons replaced by N.
 34. The compound according toclaim 23, wherein R₂ is an unsubstituted 5- to 7-membered heteroarylgroup having one, two or three ring carbons replaced by N.
 35. Thecompound according to claim 23, wherein R₂ is unsubstituted pyrazolyl ortriazolyl.
 36. The compound according to claim 23, wherein R₂ isunsubstituted pyrazolyl.
 37. The compound according to claim 23, whereinR₂ is linked via a carbon atom.
 38. The compound according to claim 23,wherein said compound is:1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-(benzylsulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((5-methyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((5,5-dimethyl-1-(phenylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,4-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-ylsulfonyl)benzonitrile,5-(1H-pyrazol-4-yl)-1-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-1H-indazole,1-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazoleor1-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole.39. The compound according to claim 23, wherein said compound is:5-(1H-pyrazol-4-yl)-1-((l-tosylpiperidin-4-yl)methyl)-1H-indazole,3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)sulfonyl)benzonitrile,1-((1-((4-(difluoromethyl)phenyl)sulfonyl)piperidin-4-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-trans-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile,rac.-trans-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((1-((4-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((1-((3-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((1-((2-fluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((1-((2,3-difluorophenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((5-methyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-1-((1-((3-methoxyphenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,rac.-cis-3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2-methylpyrrolidin-1-yl)sulfonyl)benzonitrile,rac.-cis-1-((1-((3-(difluoromethyl)phenyl)sulfonyl)-5-methylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((4-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((3-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((2-fluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((1-((2,3-difluorophenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((5,5-dimethyl-1-tosylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,1-((5,5-dimethyl-1-(m-tolylsulfonyl)pyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole,3-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrile,4-((4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)-2,2-dimethylpyrrolidin-1-yl)sulfonyl)benzonitrileor1-((1-((4-fluoro-3-methylphenyl)sulfonyl)-5,5-dimethylpyrrolidin-3-yl)methyl)-5-(1H-pyrazol-4-yl)-1H-indazole.40. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to claim 1 or 23, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 41.A method of treating a Retinoic Acid Receptor-Related Orphan Receptorregulated disease or disorder, comprising the step of administering atherapeutically effective amount of a compound according to claim 1 or23, or a pharmaceutically acceptable salt thereof, to a patient in needthereof.
 42. The method according to claim 41, wherein said disease ordisorder is an autoimmune, inflammatory, metabolic or oncologic diseaseor disorder.
 43. The method according to claim 42, wherein said diseaseor disorder is rheumatoid arthritis, psoriasis, psoriatic arthritis,polymyalgia rheumatica, multiple sclerosis, lupus, uveitis, inflammatorybowel disease, ankylosing spondylitis, vasculitis, atherosclerosis,macular degeneration, diabetes, obesity, cancer, asthma or chronicobstructive pulmonary disease.